[Show abstract][Hide abstract] ABSTRACT: Patients with semantic dementia (SD) may undergo successful relearning of object names, but these gains are usually restricted to the trained exemplars, demonstrating poor generalization. We hypothesized that generalization could be improved by restoring an item's semantic network through specific strategies that recruit the remaining personal semantic memories (conceptual enrichment therapies). We describe the case of a patient with SD who showed greater generalization of learning following a conceptual enrichment therapy than when learning items in a word-retrieval therapy. Our results suggest that enhancing an item's semantic network connections may result in improved generalization of learning in SD. A learning mechanism in the presence of compromised hippocampi is also discussed.
[Show abstract][Hide abstract] ABSTRACT: ABSTRACT Background: Discerning dementia with Lewy bodies (DLB) from Alzheimer's disease (AD) is one of the most common and challenging differential diagnoses at the memory clinic. Although the neuropsychiatric manifestations have been widely reported as one of the main key points in the differential diagnosis between these two diseases, to date no neuropsychiatric questionnaire has been specifically devised for this purpose. Methods: We administered the Neuropsychiatric Inventory (NPI) and the Columbia University Scale for Psychopathology in Alzheimer's Disease (CUSPAD) to a memory clinic sample of 80 patients with probable DLB and 85 age- and severity-matched patients with probable AD. Diagnosis of probable DLB was supported with a positive dopamine transporter SPECT scan. We examined the usefulness of these two neuropsychiatric tools designed for AD in the differential diagnosis between DLB and AD. We also investigated the correlations between psychotic symptoms and measures of cognitive and functional decline. Results: Auditory hallucinations were very specific of DLB and were usually preceded by visual hallucinations. Misinterpretation of real visual stimuli (illusions) was more frequent in DLB. Delusions were both quantitatively and qualitatively different between DLB and AD: delusional misidentifications were significantly more characteristic of DLB, while paranoid delusions did not show specificity for DLB. Conclusions: Neuropsychiatric tools are useful to discriminate DLB from AD. Hallucinations and delusions are not only more frequent in DLB than in AD but also have distinct qualitative characteristics and patterns of progression that can help clinicians to make a more accurate differential diagnosis.
International Psychogeriatrics 11/2013; · 1.89 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: BACKGROUND AND PURPOSE: Decreased plasma progranulin levels are a very specific marker for the diagnosis of frontotemporal lobar degeneration (FTLD) caused by mutations in the progranulin gene (GRN). A frequent neuroimaging pattern in this type of dementia is asymmetric cortical atrophy. The aim of this study was to screen for GRN-linked FTLD in cases with different cortical dementia phenotypes and asymmetric perisylvian atrophy. METHODS: Progranulin plasma levels were analyzed in a variety of FTLD phenotypes (n = 71), dementia of the Alzheimer type (DAT) (n = 22) and probable Lewy body dementia (n = 8), both latter groups presented with asymmetric perisylvian atrophy. A group of elderly controls (n = 29) and DAT cases with symmetric atrophy (n = 33) were also analyzed. The GRN gene was sequenced in cases with lower plasma levels. RESULTS: Four cases with clinical FTLD phenotypes and plasma levels below 70 ng/ml were found to carry different GRN mutations: M1?, C139R, a point mutation in the splice donor site of intron 3 (A89VfsX41), and a deletion in exon 9 (A303AfsX57), this latter one being a new mutation. Thirteen cases with levels between 72 and 85 ng/ml did not show pathogenic changes in the GRN gene. None of the cases with asymmetric atrophy and clinical phenotypes other than FTLD had GRN mutations. CONCLUSIONS: Asymmetric perisylvian atrophy is not likely to predict progranulin-linked FTLD unless it is associated with a consistent FTLD clinical phenotype.
European Journal of Neurology 05/2013; · 3.85 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: OBJECTIVE: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a small vessel disease of the brain caused by mutations in the NOTCH3 gene. CADASIL progresses, in some cases, to subcortical dementia with a particular cognitive impairment. Different diseases in the dementia spectrum share a central cholinergic and sensorimotor plasticity alteration. We aimed to study different intracortical circuits and sensorimotor plasticity in CADASIL patients using transcranial magnetic stimulation protocols, and to determine whether these characteristics correlated with the results of clinical neuropsychological evaluation. METHODS: Ten CADASIL patients and 10 healthy subjects were included in the study. All subjects underwent a transcranial magnetic stimulation study examining different intracortical circuits. Sensorimotor plasticity was also assessed using a paired associative stimulation and extensive neuropsychological tests. RESULTS: CADASIL patients showed a lack of intracortical facilitation, short latency afferent inhibition and sensorimotor plasticity when compared with control subjects. CADASIL patients also showed an altered neuropsychological profile. Correlation between sensorimotor plasticity and neuropsychological alterations was observed in CADASIL patients. CONCLUSIONS: These results suggest that acetylcholine and glutamate could be involved in the dementia process in CADASIL and that abnormal sensorimotor plasticity correlates with the neuropsychological profile in CADASIL patients.
Journal of neurology, neurosurgery, and psychiatry 01/2013; · 4.87 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: OBJECTIVE: Expansions of more than 30 hexanucleotide repetitions in the C9ORF72 gene are a common cause of frontotemporal dementia (FTD) or amyotrophic lateral sclerosis (ALS). However, the range of 20-30 repetitions is rarely found and still has unclear significance. A screening of our cohort of cases with FTD (n = 109) revealed 4 mutation carriers (>30 repetitions) but also 5 probands with 20-22 confirmed repetitions. This study explored the possible pathogenic correlation of the 20-22 repeats expansion (short expansion). METHODS: Comparison of clinical phenotypes between cases with long vs short expansions; search for segregation in the families of probands with short expansion; analysis of the presence of the common founder haplotype, described for expansions >30 repeats, in the cases having the short expansion; and analysis of the distribution of hexanucleotide repeat alleles in a control population. RESULTS: No different patterns were found in the clinical phenotype or aggressiveness of the disease when comparing cases with long or short expansions. Cases in both groups had psychiatric symptoms during 1-3 decades before evolving insidiously to cognitive deterioration. The study of the families with short expansion showed clear segregation of the 20-22 repeats allele with the disease. Moreover, this 20-22 repeats allele was associated in all cases with the pathogenic founder haplotype. None of 216 controls had alleles with more than 14 repetitions. CONCLUSIONS: Description of these families suggests that short C9ORF72 hexanucleotide expansions are also related to frontotemporal cognitive deterioration.
[Show abstract][Hide abstract] ABSTRACT: Sleep disturbances are prevalent in patients with Alzheimer' disease (AD), being one of the most troubling symptoms during the progression of disease. However, little research has been made to determine if impaired sleep patterns appear years before AD diagnosis. This study tries to shed light on this issue by performing polysomnographic recordings in healthy elders and patients with mild cognitive impairment (MCI). We further investigated whether changes in sleep patterns parallel memory decline as well as its relationship with the Apolipoprotein E (ApoE) ɛ4 genotype. Results showed a significant shortening of rapid eye movement (REM) sleep together with increased fragmentations of slow-wave sleep in MCI patients relative to healthy elders. Interestingly, we further showed that reduction of REM sleep in MCI patients with ApoE ɛ4 was more noticeable than in ɛ4 non-carriers. Contrary to our initial hypothesis, changes in sleep patterns were not correlated with memory performance in MCI patients. Instead, increased REM sleep accompanied enhanced immediate recall in MCI ɛ4 non-carriers. Taken together, these results suggest that sleep disruptions are evident years before diagnosis of AD, which may have implications for early detection of dementia and/or therapeutic management of sleep complaints in MCI patients.
Current Alzheimer research 03/2012; 9(3):290-7. · 4.97 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Neuropathological events featuring early stages of Alzheimer's disease (AD) appear in the entorhinal cortex (EC), subiculum (SB) and cornu ammonis 1 (CA1) of hippocampus, which may account for associative memory deficits in non-demented people with mild cognitive impairment (MCI). To test this hypothesis in vivo, we investigated whether volume changes in these regions are related to failures in associative memory in MCI as compared to cognitively normal (CN) elderly subjects. Volume changes in EC and hippocampal subfields were determined by using deformation-based morphometry techniques applied to probabilistic cytoarchitectonic maps derived from post mortem human brains. CN subjects were distinguished from MCI patients by firstly identifying local volume differences in EC and hippocampus, and then evaluating the way in which these anatomical changes correlated with performance in a non-intentional face-location association task. MCI patients not only performed worse than CN elders in building new associations, but they were further unable to benefit from semantic encoding to improve episodic binding. According to our initial hypothesis, local volume reductions in both EC and hippocampal CA accounted for group differences in associative memory whereas atrophy in CA, but not in EC, accounted for semantic encoding of associations. Two main conclusions can be drawn from the present study: i) access to semantic information during encoding does not reduce the episodic deficit in MCI; and ii) EC and hippocampal CA, two regions early affected by AD neuropathology, are responsible, at least partially, for associative memory deficits observed in MCI patients.
[Show abstract][Hide abstract] ABSTRACT: We describe the clinical phenotype of nine kindred with presenile Alzheimer's 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.
[Show abstract][Hide abstract] ABSTRACT: Neuropathological studies suggest that the basal forebrain cholinergic system (BFCS) is affected in Alzheimer's disease (AD), but there is no in vivo evidence of early damage to this system in subjects at high risk of developing AD. Here, we found that mild cognitive impairment (MCI) patients exhibited significant volume reduction of the nucleus basalis of Meynert (NbM) using recently developed probabilistic maps of the BFCS space. In addition, volumes of different magnocellular compartments varied significantly with regional gray matter atrophy in regions known to be affected by AD and were found to correlate with cognitive decline in MCI patients. Bilateral reductions of the horizontal nucleus of the diagonal band of Broca (Ch3) and frontal lobe (medial frontal, orbital, subcallosal gyrus, anterior cingulate, and middle frontal gyrus) were significantly associated with a global decline in cognitive status, whereas volume reduction of the posterior compartment of Ch4 (NbM) and temporal lobe (including hippocampus, entorhinal cortex, and amygdala) were associated with impaired delayed recall in MCI patients. These findings establish, for the first time, a link between degeneration of specific cholinergic compartments of the BFCS and cognitive-related deficits in subjects at high risk of developing AD.
[Show abstract][Hide abstract] ABSTRACT: We describe the clinical phenotype of nine kindred with presenile Alzheimer's 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 in these positions. 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.
Journal of Alzheimer's disease: JAD 11/2009; · 3.61 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Abnormal patterns of electroencephalographic (EEG) alpha oscillations in preclinical stages of dementia reveal a selective vulnerability of thalamocortical circuits to the cascade of neurodegenerative events heralding Alzheimer's disease (AD). EEG-alpha slowing characterizes both mild cognitive impairment (MCI) and healthy aging, but it remains ambiguous whether different neural mechanisms underlie this oscillatory behavior in normal and pathological senescence. In this study, we show that the strength of phase coupling and the level of phase predictability between thalamocortical and cortico-cortical EEG sources of low alpha frequency are abnormally facilitated in MCI patients when compared to healthy elderly subjects. Additionally, we found a loss of neural complexity intrinsic to both thalamic and cortical generators of lower alpha in MCI patients, which likely influenced the aberrant phase synchronization behavior between EEG-alpha sources in this high risk group of AD. Taken together, these results suggest that different neural mechanisms account for the well known slowing of alpha rhythm present in normal aging and MCI patients. Whether these anomalous neural coding mechanisms of lower alpha generation in MCI patients represent a potential electrophysiological marker of mild AD is a topic for future research.
[Show abstract][Hide abstract] ABSTRACT: Resonance in thalamocortical networks is critically involved in sculpting oscillatory behavior in large ensembles of neocortical cells. Neocortical oscillations provide critical information about the integrity of thalamocortical circuits and functional connectivity of cortical networks, which seem to be significantly disrupted by the neuronal death and synapse loss characterizing Alzheimer's disease (AD). By applying a novel analysis methodology to overcome volume conduction effects between scalp electroencephalographic (EEG) measurements, we were able to estimate the temporal activation of EEG-alpha sources in the thalamus and parieto-occipital regions of the cortex. We found that synaptic flow underlying the lower alpha band (7.5-10 Hz) was abnormally facilitated in patients with mild cognitive impairment (MCI) as compared to healthy elderly individuals, particularly from thalamus to cortex (approximately 38% higher). In addition, the thalamic generator of lower alpha oscillations was also abnormally activated in patients with MCI. Regarding the upper alpha subdivision (10.1-12.5 Hz), both controls and patients with MCI showed a bidirectional decrease of thalamocortical synaptic transmission, which was age-dependent only in the control group. Altogether, our results suggest that functional dynamics of thalamocortical networks differentiate individuals at high risk of developing AD from healthy elderly subjects, supporting the hypothesis that neurodegeneration mechanisms are active years before the patient is clinically diagnosed with dementia.
Human Brain Mapping 06/2009; 30(12):3944-57. · 6.92 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Alzheimer disease is the most common form of dementia in Western countries and the leading cause of disability in the over-65 population. Apolipoprotein E (APOE) is a multifunctional protein implied in lipid metabolism and neurobiology. Polymorphisms of the APOE gene have been associated with a variety of medical disorders, from arteriosclerosis to AD. A high frequency of the APOE epsilon4 allele has been found in patients with AD and they seem to have a higher risk of developing the disease. Various authors have suggested a possible relationship between the efficacy of cholinesterase inhibitors and the presence of the APOE epsilon4 allele. The purpose of the present study was to compare prospectively the efficacy of rivastigmine in patients with mild to moderately severe AD presenting different polymorphisms of the APOE gene on chromosome 19 and to determine if there was a difference in the response to rivastigmine treatment in AD patients with the APOE epsilon4 allele (heterozygous or homozygous) versus patients who had other forms of APOE, such as epsilon2 and epsilon3. This was an open-label, nonrandomized, multicenter study in patients over 50 years of age diagnosed with mild to moderately severe AD. The results of the analysis of this study indicate that the presence of at least one APOE epsilon4 allele does not determine a difference in the response to treatment with rivastigmine. The data indicate that knowledge of the patient's genotype is not necessary for treatment with rivastigmine. It would be interesting in the future to analyze the interaction between these 2 factors using other available anticholinesterase drugs.
[Show abstract][Hide abstract] ABSTRACT: Transient topographical disorientation (TTD) is a short-lasting inability to find one's way in a familiar environment, while the patient remains conscious and is able to recall what happened. We report the study of 10 patients with episodes of TTD, studied on the days following the last episode. The episodes of TTD could be separated into two types: the patients either reported difficulties in spatial orientation with preserved abilities to recognize landmarks and objects, or the difficulties appeared with the recognition of landmarks. Tests exploring spatial orientation, as well as higher visuoperceptive capacities were altered in most of the patients and brain SPECT showed hypoperfusion of the right hemisphere in all patients, which could also be demonstrated 2 years later in some cases. Altogether, our findings suggest that TTD is frequently associated with a more persistent right hemisphere dysfunction of unknown cause. This chronic alteration could represent either a sequel of the acute episode or a preexisting right hemisphere deficit, which inclined the acute insult to be manifested as TTD.
European Neurology 02/2002; 48(4):191-9. · 1.36 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Calcium embolism is an uncommon cause of stroke which may not be diagnosed in cases which do not involve cardiac surgery or catheterization. The emboli may come from cardiac valves or calcified atheroma of the aortic or carotid arteries.
Two patients with cerebral infarcts secondary to spontaneous calcium embolism confirmed by neuro imaging. In both cases on CT scans there were dense points corresponding to calcified material within the middle cerebral artery or one of its branches. In the first case migration of the calcified point following the course of the artery was observed.
Cranial CAT scans are essential for diagnosis of calcium embolism. Migration of the calcified point confirms the diagnosis. It is still not clear whether valve replacement is necessary in these patients and treatment with antiaggregants and/or anticoagulants is controversial.
Revista de neurologia 01/2002; 34(4):354-7. · 0.93 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: We report a family with hereditary neuropathy with liability to pressure palsies (HNPP) and chromosome 17p11.2 deletion. This family exhibits a peculiar phenotype consisting in recurrent brachial plexopathy episodes. This phenotype has to be distinguished from hereditary neuralgic amyotrophy on clinical grounds. Although the incidence of brachial plexopathy on HNPP is relatively high it is unusual as the sole symptom of the disease. It is noteworthy that in the six published families with this peculiar phenotype most of the acute episodes became evident after sleep. A greater liability of the plexus and a greater vulnerability to mechanical factors during sleep hours are the suggested mechanisms to explain this rare clinical onset. Recurrent painless brachial plexopathy when associated to generalized conduction abnormalities should suggest a HNPP.
[Show abstract][Hide abstract] ABSTRACT: Psychotic symptoms appear during the course of Alzheimer's disease, but their frequency and intensity vary according to different studies and their nature remains unsettled.
To study the frequency and intensity of psychotic symptoms in two transversal series of patients with Alzheimer's disease and analyze its relationship with the duration of the disease and severity of cognitive impairment.
This study has been carried out in patients suffering from probable Alzheimer's disease (NINDS-ADRDA criteria). The stage of the disease was determined according to FAST, and the intensity of cognitive impairment in Mini Mental State Examination was classified as mild, moderate or severe. Frequency and intensity of psychotic symptoms (delusions, hallucinations and misidentifications) were determined by means of semistructured interviews (BEHAVE-AD 78 patients and CUSPAD 69 patients). The results obtained in these three groups of patients were compared through ANOVA variance analysis and mean contrast. Variance and covariance analysis were done to determine the relationship between psychotic symptoms and other variables (degree of cognitive impairment, length of evolution and stage of the disease). For this purpose, the patients with Alzheimer's disease but without psychotic symptoms were considered as control and compared to patients with psychotic symptoms.
Nearly half the patients had psychotic symptoms. Delusions appeared earlier and were more frequent than hallucinations and misinterpretations. The more severe was the cognitive impairment, the more frequent and intense were psychotic symptoms, but the difference was significant only in cases with severe cognitive impairment. Hallucinations appeared mainly in patients with advanced dementia and were related firstly with the intensity of functional and cognitive impairment and secondly with the duration of the disease.
Mild psychotic symptoms, especially delusions, appear early during the course of Alzheimer's disease. The frequency and intensity of these symptoms increase in parallel with the functional and cognitive impairments caused by the disease. Hallucinations, which appear mainly when the dementia is severe, can be considered as an evolutive marker of the process. Psychotic symptoms differ from those occurring in other disorders, either neurologic or psychiatric in nature.
[Show abstract][Hide abstract] ABSTRACT: Arterial dissection is the cause of 20% of the stroke occurring in adults under the age of 45. The existence of recurrence has been discussed in recent studies, and the overall frequency estimated as 4% to 8%, with a risk of 1% per year. The course of the condition is usually oligosymptomatic, so that a high index of suspicion is necessary for diagnosis to be made. We consider that different connective tissue disorders and anomalies of the vascular wall predispose to dissection. It would seen reasonable to think that these same anomalies may lead to recurrence. However, this cannot always be demonstrated. A family history of dissection is also an important factor in recurrence.
We present two cases of recurrent spontaneous dissection of the carotid artery from a series of 22 patients with dissection, during the period 1990-1997. In the first case, the second dissection occurred 15 days after the first and in the second case, seven months later. In both cases the recurrence was in the contra-lateral carotid artery. In the second case the vascular tree was noted to have been formed of ecstatic, tortuous vessels.
Our series shows results similar to others published. In one of these, an underlying arteriopathy which predisposed to the condition was shown. Both followed satisfactory courses. In case 2 a high index of clinical suspicion was necessary, since the recurrence presented as headache alone.
Revista de neurologia 01/1999; 28(4):384-7. · 0.93 Impact Factor