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Background: The Consortium to Investigate Vascular Impairment of Cognition (CIVIC) is a Canadian, multi-centre, clinic-based prospective cohort study of patients with Vascular Cognitive Impairment (VCI). We report its organization and the impact of diagnostic criteria on the study of VCI., Methods: Nine memory disability clinics enrolled patients and recorded their usual investigations and care. A case report form included all vascular dementia (VaD) individual criteria for each of four sets (National Institute of Neurological Disorders and Stroke (NINDS-AIREN), Alzheimer's Disease Diagnostic Treatment Centers (ADDTC), the ICD-10 Classification of Mental and Behavioural Disorders (ICD-10), and the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV)) of consensus-based diagnostic criteria and for the Hachinski Ischemia Score (HIS). Investigators, having completed the case report form, were asked to make a clinical judgement about the cognitive diagnosis based on the best available information, including neuroimaging., Results: Of 1,347 patients (mean age 72 years; 56% women), 846 (63%) were diagnosed with dementia and 324 (24%) were diagnosed with VCI. The proportion of patients diagnosed with VaD by the diagnostic criteria was: 23.9% (n = 322) by DSM-IV, 10.2% (n = 137) by HIS, 4.3% (n = 58) by ICD-10, 3.8% (n = 51) by ADTCC, and 3.6% (n = 48) by NINDS-AIREN. Judged against a clinical diagnosis of VaD, the sensitivity/specificity of each was: DSM-IV (0.77/0.80); HIS (0.41/0.92); ICD-10 (0.29/0.98); ADTCC (0.24/0.98); NINDS-AIREN (0.42/0.995). Compared with a clinical diagnosis of VCI, sensitivities were lower for the diagnostic criteria, reflecting the exclusion of patients who did not have dementia., Conclusions: Consensus-based criteria for VaD omit patients who do not meet dementia criteria that are modeled on Alzheimer's disease. Even for patients who do, the proportion identified with VaD varies widely. Criteria based on empirical analyses need to be developed and validated.

At the Second Canadian Consensus Conference on Dementia (CCCD) (February, 1998), a group of neurologists, geriatricians, and psychiatrists met to consider guidelines for evaluation of dementia in Canada. This review paper formed a background paper for their discussion of dementia diagnosis. These experts from across the country concluded that diagnosis of suspected dementia cases continued to rest on skilled clinical assessment. Mental status exam, preferably in some quantifiable form, has become an essential part of the assessment. Selected laboratory tests are advisable in all cases (CBC, TSH, electrolytes, calcium, and glucose), but the CCCD continued to advise that CT scanning was mandatory only in selected cases where clinical findings pointed to another possibility besides Alzheimer's disease. The growing list of other diagnostic measures with potential usefulness in diagnosis of Alzheimer's disease or dementia in general was reviewed, but the evidence was judged as insufficient to support routine use of these tests by physicians. As new treatments for Alzheimer's disease become available, neurologists face new diagnostic challenges--differentiating Mild Cognitive Impairment, Frontotemporal dementias and Mixed dementias, and Lewy Body Dementia. Guidelines to aid in differential diagnosis are presented.

The relative failure of symptomatic therapeutic trials for Alzheimer's disease using non-selective cholinergic agonists brings about the need for longitudinal studies with parallel designs aimed at disease stabilization, using trophic substances or amyloid suppressors.

Nine cases of Friedreich's ataxia and seven cases of autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) were submitted to neuroradiological procedures to determine the extent of atrophic processes in the central nervous system. All cases had a computerized cerebral tomography and five were studied with pneumoencephalography. The results show a correlation between the two tests and the comparison between Friedreich's ataxia and ARSACS. In Friedreich's ataxia, the radiological signs are variable and discrete in most of the cases. In ARSACS there are constant signs of cerebellar atrophy almost limited to the superior parts of the vermis and anterior lobes.

Seventeen patients with Friedreich's ataxia or spastic ataxia were subjected to an urodynamic evaluation. Fifty-three per cent (53%) of the patients presented with urinary symptoms consisting of urgent micturition and urgency incontinence. Cystometric evaluation showed a lack of inhibition of the detrusor in 7 patients (41%). Abnormal electric hyperactivity of the external sphincter was documented in 6 cases (37.5%) by electromyography. Some hypotheses are presented to explain the etiology of these abnormal findings.

The plasma distribution of alpha-keto acids was measured in 26 subjects including 8 patients with Friedreich's ataxia, 8 with the recessive spastic ataxia of Charlevoix-Sageunay and 10 healthy volunteers. The groups were matched with regards to age, sex, weight and the study was conducted under standardized dietary intake. The result indicate significant differences in the alpha-keto acids distribution between the groups.

We have studied a large family of which seven members suffer from a progressive disease with onset in the first decade. The first symptoms were gait ataxia and clumsiness in all cases, followed by progressive development of severe distal amyotrophy reminiscent of Charcot-Marie-Tooth disease. In four patients a postural tremor which was relieved by pharmacological agents was also evident in the limbs or head. Cerebellar atrophy was confirmed on CT scan. Motor nerve conduction velocities were in the low normal range, while sensory nerve conduction was markedly decreased. All patients had impaired proprioception and vibration sense. The laboratory investigation revealed a normal CSF protein level and elevated serum bilirubin. The patients reported in this study apparently suffer from an original recessive form of spinal and olivocerebellar degeneration associated with a neuronal form of Charcot-Marie-Tooth disease.

A new syndrome of autosomal recessive spastic ataxia has been isolated in the Charlevoix-Saguenay region of Quebec. This syndrome is remarkably homogeneous and includes: spasticity, dysarthria, distal muscle wasting, foot deformities, truncal ataxia, absence of sensory evoked potentials in the lower limbs, retinal striation reminiscent of early Leber's atrophy and the frequent presence (57%) of a prolapse of the mitral valve. Biochemically, many cases show impaired pyruvate oxidation, others have hyperbilirubinaemia and some have low serum beta-lipoproteins and HDL apoproteins. These features are similar to those found in typical Friedreich's ataxia.

Dynamic muscle function was evaluated in nine patients with Friedreich's ataxia (FA) and eight with autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS). The measurement of torque throughout maximum voluntary isokinetic knee movements was used to quantitatively describe muscle weakness in the ataxic patients. Both FA and ARSACS patients were shown to have decreased dynamic strength in comparison to normal values during knee extension and flexion movements at 30 degrees/s. In the FA patients a lower torque-producing capacity was seen in the older patients. The electromyographic (EMG) activity was recorded in lower extremity muscles during the movements. In the vastus lateralis (VL), deviations from the normal EMG activation pattern were described in both groups of patients. A reduced amplitude in the EMG activity in the medial hamstrings (MH) was seen in the majority of the patients. An index of coactivation was defined by comparing the EMG activity when a muscle lengthened (antagonistic) to the EMG activity when the same muscle shortened (agonistic) during the isokinetic contractions. In comparison to normal values increased coactivation indexes were present in the VL and MH in patients of both groups. The characteristics of dynamic muscle strength and the activation of agonistic and antagonistic muscles described in the present study will provide the basis of evaluation for the effects of therapy in these patients.

Genetic linkage analysis requires the identification and documentation of large families with many affected members present, preferably in more than one generation. The IMAGE Project has been establishing a population-based Alzheimer disease (AD) registry in the Saguenay - Lac-Saint-Jean region of the Province of Quebec. The population of this region has a well-documented ancestry, with reliable genealogical records (since 1842) computerized by SOREP. We have recently begun to investigate the pedigrees of selected probands (definite, probable and possible) from the IMAGE registry in order to identify informative pedigrees for genetic linkage analysis. Interviews were carried out with close relatives of the probands (at least one informant per sibship) to identify secondary AD cases. The questionnaires used pertain to the accuracy of genealogical records, to family medical history and to a retrospective diagnosis of AD for people with cognitive deficits. By these means, we have documented a large extended pedigree in which a total of 15 individuals with cognitive deficits were ascertained over three generations. Of these cases, 7 are still living and there is autopsy confirmation in another one. Computer simulations using the program SIMLINK revealed that this is a potentially informative family for linkage analysis. Horizontal extension of the pedigree to second cousins of the proband is now being carried out. This will render the family IMAGE/1 even more informative in genetic linkage analysis studies.

Since the discovery of a significant depletion of acetylcholine in discrete areas of the brain of patients affected by Alzheimer's disease, attempts at symptomatic therapy have concentrated on acetylcholine supplementation, an approach that is based upon the efficacy of dopaminergic supplementation therapy for Parkinson's disease. Choline, then lecithin, used orally, failed to improve symptoms but the hypothesis that long-term choline supplementation might stabilize the course of Alzheimer's disease remains to be tested. Nerve growth factor may also offer that possibility. Bethanechol administered intracerebroventricularly did not help when a fixed dose was used but individual titration of more selective muscarinic agonists may prove more effective. In this article we report that tetrahydroaminoacridine (THA), given together with highly concentrated lecithin, appears to bring improvement in cognition and in functional autonomy using the Mini Mental State and the Rapid Disability Rating Scale-2 respectively, without change in behavior as reflected by the Behave-AD. Double-blind cross-over studies are in progress to establish its efficacy. Improvement in study design and means of assessment of cognition, functional autonomy and behavior have been made possible by these drug trials.

Neurotransmitter replacement therapy in Alzheimer's Disease is currently being attempted using bethanechol chloride (Urecholine) infused intracerebroventricularly with an Infusaid continuous infusion pump. The rationale of this therapy is based on the severe cortical pre-synaptic cholinergic deficit in the presence of relatively normal post-synaptic muscarinic receptor density. Patients are selected on the basis of strict clinical criteria at a functional stage 4 or 5 of Reisberg. A cortical biopsy at the time of pump and catheter implantation confirms the diagnosis by histological and biochemical examination. Pre-operative, post-operative and serial mental status assessments combined with functional ADL assessments monitor changes in behavior. A 6 months double-blind treatment period is done in every patient, who is then free to continue if he has improved on active treatment. This specific study is part of a multi-centre trial. Other therapeutic trials using somatostatin analogs, such as Sandostatin, could then be done. The biological effects of the latter compound are being studied currently in adult Green Vervet monkeys, prior to its use in Alzheimer patients. Furthermore autoradiography of bethanechol and peptides labeled with 14C administered in these animals by intracerebroventricular infusion will allow a better knowledge of their pharmacological site of action.

Twenty four ataxic patients were investigated with electromyography and nerve conduction studies. They were divided in two groups according to the area they came from, the evolution of the disease, and the clinical signs. Group I patients from the Rimouski area displayed all the clinical and electrophysiological signs of Friedreich's ataxia. Group II comprised patients who presented with a new syndrome known as the autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS). Although the clinical evolution was better in the latter, there were more electromyographic signs of denervation and the motor conduction velocities were slower. Both groups showed identical and important abnormalities in sensory nerve conduction. The results of electrophysiological studies in spastic ataxia have not been reported to our knowledge. They underline the place of spastic ataxia as distinct from Friedreich's ataxia, spastic paraplegia, and the known familial neuropathies.

To test the physiological significance in vivo of our previous in vitro finding of reduced valine dehydrogenase (VDH) activity in patients with Friedreich's Ataxia, we subjected ataxic patients and controls to an oral valine load test (1.0g) and measured the levels of branched chain alpha-keto acids in the plasma for 24 hours. We demonstrated a significantly higher peak for a alpha-keto isovaleric acid in Friedreich's Ataxia and a general trend towards higher than control values in all other alpha-keto acids measured, and at all times in the experiment. These changes are compatible with the postulated defect in regulation of the activity of VDH in this illness, but because of their small amplitude, they also indicate that a VDH deficiency is not the genetic defect in Friedreich's Ataxia.

Electroencephalographic studies have been done in two groups of hereditary ataxia: a group bearing the classical features of Friedreich's ataxia and a group clinically different described as autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS). The qualitative anomalies observed in the two groups were similar and were comparable with the data reported in the literature. However, the main difference between the two groups is the greater incidence of EEG abnormalities in the ARSACS group, which suggests more involvement of the cortical and subcortical structures. This is reinforced by the lower I.Q. performance in the latter patients. Some comments are made about focal EEG findings, behavior and I.Q. In general, EEG was not considered a valuable instrument for diagnosis since no qualitative electric pattern could be identified. With regard to prognosis, EEG cannot be used as a criterion, since there is no relation between the degree of anomalies and the severity of the disease and since EEG does not worsen with the progression of the disease.

Electronystagmographic recordings were made of oculomotor and vestibular function in 11 patients with autosomal recessive spastic ataxia of Charlevoix-Saguenay. All had horizontal gaze nystagmus, marked impairment of smooth ocular pursuit and optokinetic nystagmus, and defective fixation suppression of caloric nystagmus. Many had saccadic dysmetria, but saccade velocity was probably unaffected. Abnormalities pointing to brainstem disturbance were sparse. The findings are thought to indicate mainly diffuse cerebellar disease, with particular involvement of vermis and vestibulo-cerebellum.

We have observed a markedly decreased formation of hippuric acid after benzoic acid load in patients with typical Friedreich's Ataxia compared to normal control subjects. Since there is evidence for normal or even enhanced tauro-conjugation in the bile of patients with this disease, with a decreased G/T ratio, it is unlikely that co-factor or enzyme concentrations are the cause of this defect. We postulate decreased availability of the enzyme for glycine conjugation either to bile acids in the usual situation or to benzoic acid in the artefactual test condition. This could be due to the enzyme's preference for an increased amount of taurine substrate in the liver. The relationship of this observation to the other biochemical changes observed in Friedreich's Ataxia must still be established.

We described a cluster of 8 independent sibships of Friedreich's ataxia in the St-Fabien parish of Rimouski and have shown that they are all related within 6 generations. The study of this geographic and genetic isolate permitted the investigation of certain unusual features of the disease such as constant myopia, delayed reaction times to pain, flexor spasms, and a rapid evolution.