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.

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Sommario Scopo della presente ricerca è lo studio mediante metodiche standard di averaging, delle modificazione dell'onda d'aspettativa, sue principali componenti (complesso CNV) e tempo di reazione (RT) delle risposte motorie in pazienti affetti da forme iniziali più o meno gravi di decadimento mentale presenile idiopatico. Sono stati esaminati 19 pazienti (età media: 59.5) e 10 soggetti sani di controllo di pari età (media: 59.6). Otto pazienti presentavano un quadro clinico di demenza presenile di tipo Alzheimer (PAD), mentre in 11 soggetti era stata formulata una diagnosi di possibile forma iniziale presenile di demenza primaria (PICD) poiché non raggiungevano i criteri clinici del DSM-III e del NINCDS-ADRDA Report. Tutti i pazienti sono stati sottoposti preliminarmente and esami clinici, TAC, NMR, EEG con analisi spettrale ed a test psicodiagnostici. Per evocare il complesso CNV-RT si è adottato un parametro di stimolazione molto semplice ed idoneo anche per malati con deterioramento mentale. Oltre all'EOG ed agli RT, l'attività di tipo CNV è stata registrata da regioni frontali, centrali e parietali con referenza bimastoidea. Si sono osservate differenze significative di alcuni componenti fra i gruppi di soggetti esaminati e nella maggioranza dei dementi mancava una vera attività di tipo CNV, gli RT erano enormemente prolungati e sovente si sono registrati caratteristici “post-imperative negative variations” (PINV). I risultati ottenuti confermano l'utilità di queste metodiche nella diagnosi precoce delle demenze primarie presenili.

     

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.     

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.     

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.     

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. 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.     

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.     

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 significanty 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.

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Sammario Scopo della presente ricerca è la raccolta di dati normativi ottenuti con una nuova metodica d'analisi dell'onda d'aspettativa, delle sue principali componenti (complesso CNV) e del tempo di reazione motorio (RT) in due gruppi si soggetti normali, adulti ed in età presenile. In 20 soggetti sani (rispettivamente 10 con età media di 28.3 e 10 di 59.6 anni) per evocare il complesso CNV/RT si è adottato un parametro standard di stimolazione molto semplice ed idoneo anche per pazienti con deterioramento mentale: S1 (click)—2 sec d'intervallo —S2 (stimolo visivo)—risposta motoria con RT. Si è derivata l'attività di tipo CNV da regioni frontali, centrali e parietali. In confronto ai soggetti più giovani, modificazioni significative di alcune componenti della CNV si sono rilevate nel gruppo di soggetti in età presenile senza apparente declino delle performances comportamentali e cognitive. Tali modificazioni appaiono indicative delle fasi iniziali dei processi involutivi encefalici fisiologici associati a minimi e sublinici deficit delle risposte d'orientamento, attenzione, concentrazione, memoria a breve termine, capacità di preparazione alle risposte motorie sollecitate da S2. Vengono discusse le implicazioni cliniche ed in particolare l'importanza diagnostica di questo tipo di indagini nel riconoscimento dei primi stadi nel presenium dell'involuzione fisiologica o patologica dell'encefalo.

     

Synapse loss is greater in presenile than senile onset Alzheimer disease: implications for the cognitive reserve hypothesis

In the past, 'Alzheimer disease' (AD) referred to pathologic AD with clinical onset of dementia in the presenium, while 'senile dementia of the Alzheimer type' (SDAT) referred to senile onset AD. Because AD appears clinically homogeneous regardless of age of onset, the two subtypes in more recent years have not been distinguished. Pathologic differences have been noted, but synapse loss has not previously been compared between the two groups. Hypothesizing that synapse loss would be greater in presenile onset than senile onset AD, we compared synapse loss, as well as Alzheimer pathology in presenile and senile onset AD, using an ELISA method to quantify synaptophysin. Synaptophysin was significantly lower in presenile than senile AD in right frontal and bilateral parietal lobes. Neuritic plaque counts were significantly higher in presenile than senile AD in bilateral frontal and parietal lobes. Semi-quantitative evaluation of neurofibrillary tangles revealed significantly more tangles in bilateral frontal and parietal lobes in presenile than senile AD. Brain weight was significantly lower in presenile than senile AD. The differences in synapse loss and Alzheimer-type pathology in presenile and senile onset AD support the hypothesis that 'cognitive reserve' protects the human brain from neurodegenerative disease.     

Neuropsychological differentiation of Alzheimer's disease from vascular dementia

The purpose of this study was to determine whether cognitive test performances alone could distinguish patients with probable Alzheimer's disease from those with probable vascular dementia. Sixty-eight outpatients with clinical diagnoses of either Alzheimer's disease or vascular dementia were administered a brief battery of neuropsychological tests. Scores from the Boston Naming Test and the Hopkins Verbal Learning Test were identified as most discriminating of the groups. Seventy-seven per cent of the sample was correctly classified by a stepwise discriminant function analysis. Results of this study indicate that selected neuropsychological tests have moderate concurrent utility in the differential diagnosis of dementia.     

The referral,investigation and diagnosis of presenile dementia: Two services compared

The case notes of 28 patients with presenile dementia presenting to a neurology service were compared with 26 who had presented to a specialist old age psychiatric department (OAPD). Referrals to the former were mainly from hospital doctors for diagnostic purposes. General practitioners referred more often to the OAPD and the patients were older. The reasons were more heterogeneous, but oriented to aspects of practical management of behavioural disturbance. Patients referred to the OAPD were inadequately investigated. It is concluded that specialist old age psychiatric services in Britain have a role in the management of patients with presenile dementia but that diagnosis should be undertaken by neurologists.     

What is ‘early onset dementia’?

There are two types of dementia with early onset: (i) presenile dementias; and (ii) senile dementias with early onset. Most patients who develop dementia before 65 years of age have Alzheimer's disease (AD). The remainder are likely to have vascular dementia (VaD), frontotemporal dementia, head injury, alcohol intoxication, or metabolic disorder. Presenile dementias, caused by frontotemporal lobar degeneration, progressive supranuclear palsy, and corticobasal degeneration, usually occur in patients of presenile and are rarely seen in patients of senile age. Although the factors responsible for the accelarted onset of the illness are not fully known, genetic abnormalities appear to be important in some types of presenile dementia, such as frontotemporal dementia with parkinsonism linked to chromosome 17. Conversely, senile dementias such as sporadic AD and VaD commonly occur in patients of senile age. These disorders may also occur in patients of presenile age, although less frequently. Alzheimer's disease was originally classified as a ‘presenile dementia’. Since the 1980s, ‘senile dementia of Alzheimer type’ (SDAT) and ‘Alzheimer's disease’ have been considered to belong to the same pathological entity and both are now known as ‘dementia of Alzheimer's type (DAT)’ or merely ‘Alzheimer's disease’. Rapid progression of cognitive impairment with neuropsychological syndromes and neurological symptoms has been considered a characteristic of early onset AD. However, recently, neurological symptoms such as spastic paraparesis, seizures, and myoclonic convulsions have been reported to occur infrequently in early onset AD, although language problems and visuospatial dysfunctions are common. There are at least three dominant genes that have been identified in cases of familial Alzheimer's disease with early onset, namely the amyloid precursor gene (APP), and the genes encoding presenilin 1 (PSEN1) and presenilin 2 (PSEN2). Therefore, genetic abnormalities are important factors contributing to the earlier onset of the illness. It is also important to investigate the pathophysiological mechanism in relation to genetic abnormalities, environmental factors, physical illnesses, and metabolic disturbances to understand the processes underlying the development of dementia with early onset.     

Clinical diagnosis of presenile Alzheimer's disease: A novel approach

A national retrospective survey of hospital records was used to select those patients with presenile dementia who had undergone neuropathological examination. The National Institute of Neurological and Communicative Disorders and the Alzheimer's Disease and Related Disorders Association (NINCDS–ADRDA) clinical criteria for probable Alzheimer's disease and a Hachinski score were applied to each record before the neuropathological diagnosis was known. A discriminant analysis, which entered the criteria as variables, was performed. The diagnostic accuracy of the clinical criteria was compared before and after discriminant analysis. One thousand six hundred and seventy-one records were scrutinised of which 61 patients had undergone neuropathological examination. NINCDS–ADRDA criteria had a diagnostic accuracy of 72% (specificity 88%, sensitivity 61%) compared to 77% (specificity 80%, sensitivity 75%) after analysis. NINCDS–ADRDA criteria together with the Hachinski score had an accuracy of 72% (specificity 61%, sensitivity 88%) compared to 83.6% (specificity 76%, sensitivity 89%) after analysis. Variables of highest discriminating value were the Hachinski score, presence of coexistent neurological disease and presence of coexistent systemic disease. The results highlight limitations of current clinical criteria used to diagnose Alzheimer's disease and suggest that substantial improvements are possible.     

Acetylcholinesterase activity in cerebrospinal fluid of patients with Alzheimer's disease and senile dementia

Acetylcholinesterase (AChE) in the cerebrospinal fluid (CSF) from patients with Alzheimer-type dementia and control subjects was analyzed by centrifugation on a sucrose density gradient, and by column chromatography on Sephadex G-200. The sedimentation coefficient and molecular weight of CSF AChE were calculated as 10S and 380,000, respectively, which corresponded to those of G4 isozyme in the brain. Other isozymes of AChE were not detected in the CSF of either patients with Alzheimer-type dementia or the controls. Sufficient activity of AChE was observed in the CSF of a patient with familial pseudocholinesterase deficiency, although the pseudocholinesterase activity was not found either in the serum or in the CSF. CSF AChE activity in control subjects increased with advancing age (P less than 0.02). AChE activity in the CSF was significantly lower in patients with presenile dementia (Alzheimer's disease), compared with age-matched control subjects (P less than 0.001). However, AChE activity in the CSF showed a wide variation among patients of Alzheimer-type dementia with a late onset (senile dementia).     

Cerebral dysfunction in alcoholism and presenile dementia

Fifteen chronic alcoholics and 15 presenile patients were matched in pairs with regard to their mean hemisphere cerebral blood parameters - an index of brain metabolism. The distribution of the regional cerebral blood flow was similar in the two groups. The alcoholics performed significantly better in all psychometric tests than the presenile patients and more alcoholics than presenile patients were still employed and working. Nine presenile patients and one alcoholic showed symptoms indicating brain stem dysfunction. The measurements of the cerebral blood flow were made at rest while the psychometric testings and the evaluation of the social performace gave information about the brain at work. It is suggested that cerebral dysfunction in alcoholics to some extent can be partly overcome by brain activation procedures. In contrast, the defects of higher mental functions in presenile dementia cannot be compensated for.     

Contingent negative variation and regional cerebral blood flow in senile dementia and cerebral aging

Relationships between contingent negative variation (CNV) amplitude, regional cerebral blood flow (CBF), mini mental status examination score (MMSE) and reaction time (RT) have been studied in young subjects, non-demented old subjects and patients with primary degenerative senile dementia. Significant correlations have been found between CNV amplitude and global CBF, MMSE score and reaction time. Factorial analysis has shown 3 factors weighted respectively by MMSE and CNV, antero-posterior ratio fort left hemispheric CBF and age, and antero-posterior ratio for right hemispheric CBF and reaction time. Discriminant analysis has shown 2 discriminant functions differentiating young from old subjects with 90% accuracy and demented from non-demented patients with 75% accuracy.     

Presenile non-Alzheimer dementia with motor neuron disease and laminar spongiform degeneration

We describe the clinicopathological findings in three autopsy cases of presenile dementia with motor neuron disease. These patients had a relatively rapid course involving dementia and muscle weakness with a distal pattern of atrophy in the upper extremities. Postmortem examination revealed features of motor neuron disease and spongiform cortical degeneration. The latter change was most marked in the second layer of the frontal or temporal cortex and included minimal to mild neuronal cell loss and mild to moderate gliosis. In this report we relate these patients' laminar spongiform degeneration to three other conditions; frontal lobe dementia, primary progressive aphasia and dementia lacking a distinctive histology. These three conditions and presenile dementia with motor neuron disease may fall within the spectrum of the non-Alzheimer type frontotemporal degenerative dementia.     

Levodopa treatment of presenile dementia

In Parkinson's disease as well as presenile dementia there is a dopamine deficit in the basal ganglia. Extrapyramidal symptoms are common in presenile dementia, and dementia is a common trait in Parkinsonism. It is reasonable to suggest a partial common etiology and pathophysiology, and the logical consequence is an investigation of levodopa substitution in presenile dementia. Unitil now very few reports of such studies have been published. The investigations have been uncontrolled or carried out on small or inhomogeneous materials. This investigation is triple-blind, clinically controlled, and the material is very homogeneous. After 6 months' levodopa treatment no significant effect is shown either on a broad spectrum of psychiatric items or in cognitive functioning. This negative result is discussed. The probability of a specific Parkinson dementia is mentioned and the significance of the modifying effect of an imbalance in other transmitter systems is emphasized.     

Unusual Case of Presenile Dementia–A Clinical Case Report

Abstract: A predominant disturbance of expressive language function was the first and outstanding manifestation of presenile dementia in a 40-year-old female. A CT-scan revealed a moderate atrophy in the frontal, triangular and opercular regions. This is an unusual case of presenile dementia with an aphasic disturbance of language as the initial symptom.     

Neuropsychiatric studies in a family with presenile dementia different from Alzheimer and Pick disease

ABSTRACT: We have studied a family in which 14 persons among 73 are or have been suffering from presenile dementia. Post mortem examination showed atrophy but no sign of any known demential syndrome. Cerebral blood flow measured in the late stage of disease was low, but with no characteristic pattern in flow distribution. In one patient in the initial stage of disease, the cerebral blood flow was unexpectedly increased. The patients with presenile dementia in this family did not reveal pathological signs of any known demential syndrom and showed CBF-changes not earlier reported. Moreover, contrary to widely held views we have evidence that dementia may be connected to a high blood flow at least in the initial state. An increased blood flow was also seen in seven of ten well functioning first degree relatives, in some cases along with cerebral atrophy and/or psychological tests with signs of dementia. Are these people going to develop manifest dementia later in life?     

Platelet MAO-B activity and vitamin B12 in old age dementias

Platelet MAO-B activity, serum vitamin B₁₂ levels, and plasma folate were measured in patients suffering from presenile (AD) and senile (SDAT) dementia of Alzheimer-type, and vascular dementia (VD). MAO-B was higher in the SDAT group than in AD and controls. An inverse relationship between MAO-B activity and vit. B₁₂ levels was documented in the whole group and in each category studied; furthermore, MAO-B was positively related to age. All the patients were then divided into two groups, according to vit. B₁₂ levels (Group I: <200 pg/mL; Group II: ≥200 pg/mL); Group I showed a significantly higher MAO-B activity with respect to Group II. The results indicate the existence of a negative association between platelet MAO-B activity and serum levels of vitamin B₁₂ and confirm the existence of biological differences between presenile and senile dementia of Alzheimer type.