CT and MR imaging of neuroaxonal leukodystrophy presenting as early-onset frontal dementia.

CT and MR imaging showed diffuse changes of the frontal white matter and genu of the corpus callosum with minimal atrophy and no contrast enhancement in a 41-year-old woman with progressive dementia. Brain biopsy disclosed axonal spheroids and gliosis in the white matter without macrophage or inflammatory infiltration or vessel abnormalities consistent with neuroaxonal leukodystrophy. This disease can be suspected on CT and MR imaging findings but requires neuropathologic examination to be diagnosed.

The effects on auditory neurocognitive evoked responses and contingent negative variation activity of frontal cortex lesions or ablations in man: three new case studies.

Our previous research in patients with extensive surgical ablations of the prefrontal cortex contradict the hypothesis of some authors that the generators of several auditory event-related potentials (ERPs) (N100; P200; N200; P300; SW), recordable in humans with depth/scalp electrodes and MEG over the prefrontal dorsolateral cortical areas, are essentially located in medial prefrontal and anterior cingulate-limbic cortices. Using a standard CNV paradigm, 21 EEG electrodes and topographic mapping analysis, the post-warning (S1) auditory N100a b c, P200, P300 (binaural clicks) and CNV activity were recorded in three additional patients after extensive dorsolateral and/or medial prefrontal cortex ablations, verified through CT/MRI examinations. No true post-S1/CNV components were recordable over the ablated frontal areas, only sporadic volume-conducted ERPs probably generated in the temporo-parietal lobes or posterior cingulate gyrus. For one of these patients, after excision of a vast right frontal epileptogenic cortical region (including extensive dorsolateral areas, but sparing the fronto-medial cortex and anterior/middle cingulate gyrus), no post-S1/CNV components were recordable over the ablated regions. These latest observations again indicate that independent neuronal generators of several post-S1 auditory and CNV components are located in the dorsolateral supramodal premotor/prefrontal cortical areas which are directly, ipsilaterally connected to the uni/multimodal temporo-parieto-occipital sensory and associative regions through the long, two-way, fairly superficial, superior arcuate-longitudinal and deeper superior and inferior occipito-frontal bundles. Clear and almost constant differences in the latency of some post-S1 N100 subcomponents (especially the time-lapses between onset and the highest amplitude of the N100 a and c) over various posterior, central and anterior cortical areas sequentially involved, roughly measured in 10 normal subjects along the scalp and with MRI cerebral imaging, may probably be accounted for by the transcortical homohemispheric conduction time, which varies in our scalp recordings from 1 cm/0.74-1.28 ms, mean approximately 1 cm/1.02 ms ( approximately 9.8 ms).

Presenile primary cognitive decline or Alzheimer's dementia: 7-year clinical and neuropsychological follow-up.

Early diagnosis of presenile Alzheimer's disease (AD), which would serve for prognosis and for guiding choices of treatment, is still an important, difficult task for the clinical neurologist. We studied 24 patients, 12 of whom had minor cognitive impairment or questionable dementia (PICD) and 12 who met NINCDS-ADRDA criteria for presenile AD (PAD). Using clinical, neuropsychological, neurophysiological and neuroradiological methods, we followed the patients up to two disease end-points: death or untestable condition. This paper concentrates on the main clinical and neuropsychological findings relative to these two end-points. All PAD patients evolved into clinically evident Alzheimer-type dementia, became untestable within 60 months and died within 72 months. Only 3 of the PICD patients became demented; 2 of them died during the follow-up and 1 died eight months later. The other 9 PICD patients showed only moderate cognitive decline, compatible with normal aging processes. Neurophysiological and neuroradiological findings might be an important tool for arriving at a correct early diagnosis, when they are assessed with clinical neuropsychological data.

Decreased EEG microstate duration and anteriorisation of the brain electrical fields in mild and moderate dementia of the Alzheimer type.

Spatially oriented segmentation allows researchers to break down the continuous stream of the ongoing EEG into microstates with stable topography of the brain electrical landscapes. The resulting microstates were shown to be related to conscious mental experience as well as to psychiatric disorders typically associated with thought disorders. In the present study, the microstates of the resting EEG of patients presenting with mild or moderate probable dementia of the Alzheimer type (DAT) were investigated. A significant anteriorisation of the centers of gravity of the microstate fields, an increase of the microstates' optimal window size and a reduced duration of sustained microstates were found. These differences were statistically more robust than the typical changes in the frequency domain (diffuse slowing) and were significantly correlated with the cognitive decline. The adaptive spatial segmentation into microstates is discussed as a method to extract meaningful EEG parameters for the early diagnosis and staging of Alzheimer's disease.

Brain electrical activity (quantitative EEG and bit-mapping neurocognitive CNV components), psychometrics and clinical findings in presenile subjects with initial mild cognitive decline or probable Alzheimer-type dementia.

Clinical, neuropsychological and neuropsychophysiological data (Q-EEG, ERPs and CNV/RT activity) were obtained from 24 patients who had more or less severe presenile primary cognitive decline without depression, and compared with similar data from 10 age-matched healthy volunteers (mean age, 59.4 years). All of the patients (15 M and 9 F; mean age 59.6 years) were selected according to the DSM III-R, ICD-10 and NINCDS-ADRDA criteria and underwent CT and MRI scanning, in addition to a standard clinical examination, a battery of psychometric tests, spectral EEG, and bit-mapped CNV complex and RT to S2 analyses. Twelve of the 24 patients presented an initial presenile idiopathic cognitive decline (PICD) but did not wholly fulfil the clinical and neuropsychological criteria for primary dementia or for a diagnosis of probable AD; the remaining 12 patients showed characteristic clinical signs and symptoms of a very probable early stage of presenile Alzheimer-type dementia (PAD). ANOVA, correlational and discriminant analyses of the neuropsychological test scores, and the neurophysiological and RT to S2 data revealed 22 highest-ranked between-group discriminant factors (all with a significance level of p < 0.01). The conclusive discriminant analysis retained 13 of these factors as final canonical functions, and these showed a 97% grouping accuracy (33 of the 34 subjects examined); the same percentage of correct classifications was also achieved using only the 15 best indicators in the group of CNV/RT findings. Using both of these sets of highest-ranked discriminators, all of the normal subjects and all of the PAD patients were correctly classified; only 1 PICD patient was misclassified as normal when the first group of 13 factors was used, and another PICD patient was misclassified as PAD using the second group of 15 factors. Our findings suggest that, providing they are correctly performed and interpreted, these non-invasive techniques may be an important tool for identifying incipient stages of presenile Alzheimer-type dementia.

Cognitive potentials: ipsilateral corticocortical interconnections in prefrontal human cortex ablations.

The research deals with the possible role of the essentially monosynaptic bidirectional corticocortical connections between occipito-temporo-parietal association cortical areas and frontal areas in the genesis of some contingent negative variation (CNV) components, especially on the supramodal dorsolateral prefrontal regions. With standard and topographic mapping methods of analysis, the multicomponent CNV complex formation was examined in 7 patients with extensive frontal cortex ablations exactly identified through CT/MRI examinations, and in 10 normal subjects. On the scalp over the ablated frontocortical areas, no consistent post-warning auditory N100 a-b-c, P200, P300, early and late CNV components were recordable. The hypothesis is proposed that the bidirectional ipsilateral long-distance pathways which interconnect uni-polymodal occipito-temporo-parietal cortical areas to prefrontal ones, in particular the arcuate-superior longitudinal and superior/inferior occipito-frontal fasciculi, play an important role in the genesis of several CNV complex components, especially the multicomponent post-S1 auditory N100. The posteroanterior sequential latency differences of these neurocognitive components, roughly measured along the scalp or on MRI imagings, is probably accounted for by the transcortical ipsilateral conduction time of about 1 cm/ms (10 m/s).

Cortico-cortical connections, non-linear multicolumnar parallel distributed networks and memory processes in humans. A review.

This review outlines the knowledge gained in the last 50 years concerning the neuroanatomy and neuro-psychophysiology of memory processes in humans. The first part traces the history of the most important findings from ablations of specific cerebral structures and/or stimulations performed on numerous patients using different surgical and neurophysiological methodologies. The interpretation of these findings is discussed. The most recent hypotheses on the neuronal substrates likely to be involved in memory and recall processes are then presented. In particular the concept of parallel distributed non-linear multicolumnar cortical networks is described as well as the recent hypothesis concerning the chaotic oscillatory properties of these complex non-linear neuronal systems which are said to behave as chaotic deterministic attractors.

Changes in bit-mapped contingent negative variation (CNV) activity due to initial normal involutional processes of the human brain.

Bit-color mapped multicomponent CNV complexes and RTs to S2 evoked with a simple warned CNV/RT paradigm were recorded and measured in 20 selected right-handed very healthy volunteers (10 young adults and 10 presenile subjects, mean age 28.3 and 59.6, respectively). EEG and CNV components (post S1, N1, P2, P3; early CNV; N1200; late CNV; CNV resolution) were recorded from Fz, C3, Cz, C4, P3, Pz, and P4 referenced to linked mastoid electrodes. EOG, RT and stimuli were also recorded. The presenile group differed significantly from the younger group in the auditory post-S1 N1 and early (O-wave) and late (P-wave) CNV complex components. A progressive amplitude reduction limited to frontal leads between O-wave and P-wave, the lowest point being reached in the P-wave, was characteristic in the presenile group. Moreover, presenile subjects showed relatively flat CNV waveshapes of low amplitude and, on the whole, performed a little less well than young ones. This finding suggests that the statistically significant changes in auditory post-S1 N1 and CNV activity recorded in our presenile subjects, without any appreciable deficits in behavioral or mental performance, could be alerting signs of early brain involutional processes related to minimal and subclinical decline in orienting, attentiveness and response preparation capabilities. If such is the case, and it could be confirmed in a larger sample of very healthy subjects, these age-related changes in the presenium might prove to be of considerable practical importance for clinical research.

Effect of physiological and pathological aging processes on topographic bit-mapped cognitive evoked potentials in presenile subjects.

Bit-mapped multicomponent CNV complex and reaction time (RT) were recorded and measured in 24 presenile patients with initial symptoms of very mild to moderately severe primary mental deterioration without depression, and in 10 age-matched controls. All patients underwent CT and MRI examinations, EEG spectral analysis and a battery of psychometric test. Significant group differences were obtained for measures of some post-S1 ERP and CNV components, particularly of the post-S1 N1b, P300 and early and late pre-S2 CNV. P300 with increased latency, no significant CNV activity, very prolonged RTs, EEG slowing down and diffuse brain atrophy were observed in the majority of patients with probable presenile Alzheimer's dementia. These results suggest that CNV/RT and EEG activity changes similar to those observed in our patients may constitute a valuable clue for the study of brain dysfunction in the early stage of presenile idiopathic cognitive impairment.

Topographic CNV activity mapping, presenile mild primary cognitive decline and Alzheimer-type dementia.

The CNV complex evoked with a standard paradigm (S1-2 sec-S2-motor response) and reaction time (RT) to the imperative signal (S2) were recorded and measured in 12 patients with initial presenile idiopathic cognitive decline (PICD), 12 with presenile Alzheimer-type dementia (PAD) and 10 healthy age-matched controls. Significant group differences were obtained for measures of some CNV components, particularly of the late pre-S2 CNV. No significant CNV activity, very prolonged RTs and sometimes characteristic post-imperative negative variations (PINV) were observed in the majority of patients with PAD. These results suggest that similar CNV complex and RT changes to those observed in our patients may constitute a valuable clue in the study of pathophysiological brain functioning in the early stages of presenile idiopathic mental deterioration.

Applications of bit-mapped "cognitive" potentials (ERPs) in clinical neurophysiology--CNV complex in patients with destruction of the dorso-anteromedial bidirectional thalamo-prefrontal pathways.

We discuss the most important current problems relative to the recording procedures and methods of analysis, using inter alia spatio/temporal topographic maps, of some cognitive event-related potentials (CNV complex etc.) in normal and pathological conditions. After these initial premises of neurocognitive electrophysiology, we summarize the results for 8 patients in whom we examined the effects on CNV activity formation of surgical or spontaneous bihemispheric deafferentation of prefrontal/premotor cortical associative areas. These observations bear out the hypothesis that the bidirectional homohemispheric long and short distance pathways connecting associative parieto-temporal and occipital cortical areas to the prefrontal ones, play an important role in the genesis of the long-latency cognitive event-related potentials.

Cognitive event-related potentials and reaction time in presenile subjects with initial mild cognitive decline or probable Alzheimer-type dementia.

The so-called contingent negative variation (CNV) is a slow brain potential representing a complex of variously overlapped "endogenous" components of behavior related to different reasonably well-known neurocognitive processes. CNV complex evoked with a standard paradigm (S1-2 sec-S2-motor response) and reaction time (RT) to imperative signal (S2) were recorded and measured in 11 patients with initial presenile idiopathic cognitive decline (PICD), 8 with presenile Alzheimer-type dementia (PAD) and 10 healthy age-matched controls. Significant group differences were obtained for measures of some CNV components, particularly of the late pre-S2 CNV. No significant CNV activity, very prolonged RTs and sometimes characteristic post-imperative negative variation (PINV) were observed in the majority of patients with PAD. These results suggest that CNV complex and RT changes similar to those observed in our patients may constitute a valuable clue for the study of pathophysiological brain functioning in the early stages of presenile idiopathic mental deterioration.

Diagnosis and follow-up of mitochondrial encephalomyopathy: CT and MR studies.

A case of mitochondrial encephalomyopathy followed by CT and magnetic resonance is reported. Magnetic resonance showed the cortical lesions of the disease better than CT but CT was superior in demonstrating basal calcium deposits, a nearly constant element of the disease.

Age differences in contingent negative variation activity of healthy young adults and presenile subjects.

20 selected right-handed very healthy subjects (10 young adults and 10 presenile subjects mean age 28.3 and 59.6) were tested for CNV activity with a simple warned reaction time (RT) paradigm. EEG and CNV components (post-S1, N1, P2, P3; early CNV; N1200; late CNV; CNV resolution) were recorded from Fz, C3, Cz, C4, P3, Pz, and P4 referenced to linked mastoid electrodes. EOG, RT and stimuli were also recorded. The presenile group differed significantly from the younger group in the auditory post-S1 N1 and P3, and in the early (O-wave) and late (P-wave) CNV complex components. A progressive amplitude reduction only in frontal leads between O-wave and P-wave with the lowest point being reached in the P-wave was characteristic in the presenile group. Further, presenile subjects showed relatively flat CNV waveshapes of low amplitude and, as a whole, performed a little less well than young persons. This finding suggests that the statistically significant changes in post-S1 EPRs and CNV activity recorded in our presenile subjects, without appreciable deficits in behavioral and mental performance, could be alerting signs of early brain involutional processes related to minimal and subclinical decrement of orienting, attentiveness and response preparation capabilities. If such is the case and it could be confirmed in a larger sample of very healthy subjects, these age-related changes in the presenium could be of considerable practical importance for clinical and research applications.

Long-term treatment with sodium valproate: monitoring of venous ammonia concentrations and adverse effects.

Adverse effects and venous blood ammonia concentrations were monitored over a period of 7 months in patients with epilepsy treated with valproate (VPA). During the 1st, 4th, 12th, 20th, and 28th weeks of therapy, blood samples for analysis of ammonia and anticonvulsants were taken immediately before the morning dose of VPA as well as 2 h after dosing. In all, 40 patients completed the follow-up; 16 of these (Group 1) received VPA alone, while the remaining 24 (Group 2) were treated simultaneously with VPA and other anticonvulsants (phenobarbital, phenytoin, and/or carbamazepine). In Group 1 patients, a slight though significant increase in ammonia concentrations was found during long-term VPA treatment; this trend was even more pronounced in Group 2 patients. The difference between postdose and predose ammonia levels in Group 2 patients was significant at each of the five follow-up examinations. In contrast, no such difference was demonstrated in patients of Group 1. VPA concentrations were found to be consistently higher in Group 2 patients than in Group 1. Twenty-three patients complained of various long-term adverse effects, while the other 17 remained symptom-free. The adverse effects reported included drowsiness, tremors, weight gain, hair loss, and gastrointestinal symptoms. Our data confirm the previously suggested hypothesis that changes in venous blood ammonia are particularly evident in patients taking VPA in combination with other antiepileptic drugs, such as phenobarbital and phenytoin.

Contingent negative variation and reaction time in patients with presenile idiopathic cognitive decline and presenile Alzheimer-type dementia. Preliminary report on long-term nicergoline treatment.

Up to date 6 patients with initial presenile idiopathic cognitive decline (PICD) and 5 suffering from a presenile Alzheimer-type dementia (PAD) with a mean age of 59.5 were admitted to the trial. The 6 PICD patients were assigned to a double-blind nicergoline/placebo 6-month course with an oral dose of 30 mg twice a day. PAD patients were treated in an open design (nicergoline oral dose 30 mg twice a day) for at least 6 months. Until now only 4 PICD and 3 PAD patients have been treated regularly for 6 months. Two of 4 PICD patients showed a progressive enhancement of contingent negative variation (CNV), shorter reaction time (RT) and an improvement of clinical status. The other 2 PICD patients, on the contrary, showed a progressive mild worsening of CNV-RT and clinical patterns. The double-blind trial is not yet completed. CNV activity, RTs and clinical patterns progressively improved also in 2 PAD patients while in the 3rd they remained nearly unchanged or minimally worse during the 6-month treatment. The positive nicergoline effect on CNV-RT and clinical status noted in our patients appeared similar to that observed by other authors with DHEMT in patients with senile dementia of Alzheimer type. No adverse drug-related reactions were seen.

Lack of relationship between sodium valproate-induced adverse effects and the plasma concentration of its metabolite 2-propylpenten-4-oic acid.

The concentrations of valproic acid (VPA) and of its metabolites 3-oxo-VPA and 4-en-VPA were measured in the plasma of 12 selected epileptic patients 1, 2, 3, and 4 h after administration of a loading dose of VPA. Four of the patients, all on polytherapy, had had short-term adverse effects during chronic VPA treatment, and in them there has been abnormal NH3-values after a test doese of VPA. Eight patients (4 on monotherapy and 4 on polytherapy) had been free from adverse effects. No significant difference in the VPA, 3-oxo-VPA and 4-en-VPA concentrations was found between the three groups of patients. Accumulation of 4-en-VPA is not involved in the short-term adverse effects and hyperammonaemia induced by VPA.