The number of pregnancies is a risk factor for Alzheimer's disease.

Epidemiological data show a higher prevalence of late-onset Alzheimer's disease (AD) in women. The estrogenic deficiency in the post-menopausal period is suspected to be the cause of the gender-related risk of the disease, but studies on the estrogenic therapy and occurrence of AD were not consistent and sometimes contradicting. The aim of this study is to investigate whether a higher exposure to endogenous estrogens is associated with lower risk of dementia or not. Two hundred and four AD patients and 201 control women were considered. By interviews, we evaluated different variables, indirectly correlated to estrogenic natural exposure, as well as educational level and head trauma. These data were correlated in the AD group with the disease progression, as well as with the age at onset. Unexpectedly, we found a significant higher number of pregnancies in the AD than in the control group. Within the AD cases, the number of lifetime pregnancies is related to an earlier onset of the disease. As previously reported, we confirmed that the educational level is a protective factor and that major head trauma represents a risk factor in developing AD. The higher number of pregnancies and a less frequency of nulliparous women, indirectly relate the AD group to a higher estro-progestinic exposure. These findings suggest that it is the increase of progesterone or estrogens level--and not the estrogens decrease, as previously indicated by other authors--that could play a role in the Alzheimer's pathology.

Increase of cdk5 is related to neurofibrillary pathology in progressive supranuclear palsy.

BACKGROUND: Progressive supranuclear palsy (PSP) is characterized by a pure neurofibrillary tau pathology involving mainly basal ganglia and brainstem nuclei. In addition to a haplotype of the tau gene potentially favoring tau aggregation, lipoperoxidation has been shown to be associated with PSP tau pathology. OBJECTIVE: To analyze cdk5/p35 complex, a kinase that regulates neurite outgrowth, as a potential cellular mechanism underlying tau phosphorylation in brain tissues from PSP and control cases and comparatively in cerebral cortex from subjects with AD. METHODS: Cdk5/p35 protein levels and distribution were evaluated by immunoblotting and immunocytochemistry in brain regions from seven PSP, six AD, and seven control cases, with similar postmortem intervals. RESULTS: Total cdk5 protein levels were significantly increased by more than threefold in PSP tissue and were augmented in PSP neurons, codistributed with tau immunoreactivity. P35, the regulatory subunit of cdk5, was degraded by postmortem proteolysis to the same extent in PSP, AD, and control tissues. CONCLUSIONS: The proteolysis in vivo of p35, the regulatory subunit of the kinase, is not ascertainable because it is masked by its postmortem degradation. The study, however, indicates that in PSP, the alteration of cdk5 is different from that described in AD and suggests that the absence of amyloid beta protein deposition may account for the different pathways responsible for the same kinase activation.

Motor recovery following stroke: a transcranial magnetic stimulation study.

OBJECTIVES: To verify the usefulness of early recording of motor evoked potentials (MEPs) in predicting motor outcome after stroke and to investigate the neural mechanisms underlying functional recovery following stroke. METHODS: We performed a comparative analysis of the behaviour of motor responses evoked by transcranial magnetic stimulation (TMS) of the ipsilateral and contralateral motor cortex in the affected and unaffected thenar muscles of 21 consecutive patients with acute stroke. RESULTS: According to the behaviour of MEPs in the affected muscles, patients could be divided into 3 groups: (a) 10 subjects with absent responses to TMS of both the damaged and undamaged hemisphere, whose motor recovery was poor and related to the size of MEPs on the normal side; (b) 5 subjects with larger MEPs upon TMS of the ipsilateral (undamaged) than of the contralateral (damaged) cortex, whose good recovery possibly resulted from the emergence of ipsilateral pathways; (c) 6 subjects with larger MEPs in the affected than in the unaffected muscles, whose good recovery was possibly subserved by alternative circuits taking over cortical deafferentation. CONCLUSIONS: Early MEP recording in acute stroke provides useful information on the clinical prognosis and the different mechanisms of motor recovery.

Intracortical inhibition after paired transcranial magnetic stimulation depends on the current flow direction.

OBJECTIVES: To assess whether cortico-cortical inhibition (CCI) induced by paired-pulse transcranial magnetic stimulation (TMS) is influenced by 'preferential' or 'non-preferential' activation of the motor cortex. METHODS: Paired-pulse TMS (conditioning-test paradigm with interstimulus intervals of 2-5 ms) with a round coil centered over the vertex was performed in 10 normal subjects using opposite current flow directions. The amount of CCI in the opponens pollicis and first dorsal interosseus muscles was determined. RESULTS: When a clockwise current was induced in the brain (side A of the coil uppermost) a 'preferential' activation of the left hemisphere (right hand muscles) was observed, but the suppression of the test response by the conditioning stimulus (i.e. the CCI) was significantly greater in the left hand muscles. The situation was reversed when an anticlockwise current (side B of the coil uppermost) was induced in the brain. These effects occurred independently of the interstimulus interval, or of the absolute conditioning stimulus strength. CONCLUSIONS: CCI is more effective in the 'non-preferentially' stimulated hemisphere, and the neural elements generating the indirect I3 wave are more sensitive to intracortical inhibition than those generating the I1 wave.

Changes of intracortical inhibition during motor imagery in human subjects.

Paired-pulse transcranial magnetic stimulation with a conditioning-test paradigm was used to assess changes of corticocortical inhibition and facilitation during mental simulation of sequential finger movements in normal subjects. The cortico-cortical inhibition (at interstimulus interval, ISI, of 3 ms) was significantly reduced in the relaxed opponens pollicis (OP) muscle during motor imagery, regardless of the absolute size of the test motor evoked potential. The amount of cortico-cortical inhibition was similar to that observed during a mild voluntary contraction of the OP. No change of cortico-cortical facilitation was observed at the ISI of 12 ms. The data support the hypothesis that similar neural structures, including the primary motor cortex, are activated during both mental simulation and actual execution of motor activities.

Comparison of intracortical inhibition and facilitation in distal and proximal arm muscles in humans.

1. Cortico-cortical inhibition and facilitation induced by paired transcranial magnetic stimulation (TMS) of the human motor cortex were investigated in the distal muscle opponens pollicis (OP) and the proximal muscle biceps brachii (BB) of normal subjects. 2. The test response evoked by TMS (125 % of motor threshold, MTh) in the relaxed OP and BB muscles was inhibited by a conditioning TMS (80 % of MTh) at short interstimulus intervals (ISIs; 2-5 ms) and facilitated at longer ISIs (10-25 ms). The test response was significantly less inhibited at short ISIs and more facilitated at long ISIs in the BB than OP. 3. The MTh at rest was significantly lower for the OP than for the BB, indicating a greater excitability of OP cortical area. However, the above pattern of inhibition and facilitation was preserved both when the stimulus intensity was adjusted to evoke test responses of matched size in the two muscles and within an ample range of conditioning stimulus intensities. 4. The use of a circular coil or a focal figure-of-eight coil produced no qualitative differences in the pattern of inhibition and facilitation in either muscle. 5. The significant difference in MTh between muscles was lost during voluntary activation. In both muscles, pre-innervation abolished the cortico-cortical facilitation and reduced the cortico-cortical inhibition. However, the latter remained larger in the OP than BB muscle. 6. We suggest that the different potency of intracortical inhibitory and facilitatory circuits directed towards distal and proximal arm muscles is related to their diverse prevalent functions.

Very high prevalence of right-to-left shunt on transcranial Doppler in an Italian family with cerebral autosomal dominant angiopathy with subcortical infarcts and leukoencephalopathy.

BACKGROUND AND PURPOSE: Cerebral autosomal dominant angiopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an autosomal dominant hereditary disease whose clinical expression is a stepwise subcortical vascular dementia. Initial presentation of the disease involves transient or stabilized focal neurological deficits, migraine and mood changes. Recently, a high prevalence of right-to-left shunt (RLS) due to patent foramen ovale has been reported in subjects with migraine. The aim of our study was to determine the prevalence of RLS in CADASIL with and without migraine. METHODS: We performed transcranial Doppler with gaseous contrast in 5 members of an Italian family with CADASIL, diagnosed by means of genetic and skin biopsy criteria. We then compared the prevalence of RLS in 40 consecutive subjects with juvenile stroke, 80 asymptomatic subjects affected by migraine with aura and 50 normal controls. RESULTS: A very high prevalence of RLS was found in CADASIL patients (4/5, 80%), as opposed to young subjects with ischemic stroke (15/40, 37%), asymptomatic subjects with migraine (32/80, 40%) and normal controls (8/50, 16%). All the subjects with CADASIL and migraine (4/4) showed RLS. The difference between CADASIL patients and controls was highly significant (p = 0.006). CONCLUSIONS: We suggest an association between CADASIL and RLS, possibly due to the abnormal development of the endocardial cushion influenced by Notch 3 mutation. Our hypothesis needs to be tested in larger samples.

Plasma levels of amyloid beta-protein 42 are increased in women with mild cognitive impairment.

BACKGROUND: Accumulation in the brain of small aggregates of amyloid beta-protein 42 (Abeta42) is the major pathogenic event of Alzheimer disease (AD). In familial early-onset AD this event is likely the result of Abeta42 overproduction; in the most common sporadic late-onset form of the disease the mechanisms of Abeta42 accumulation are unknown. METHODS: To address this issue the authors analyzed plasma levels of Abeta42 in 88 elderly patients with amnestic mild cognitive impairment (MCI), chosen as paradigm of preclinical sporadic AD. RESULTS: The authors found a significant increase of Abeta42 plasma levels in women with MCI, in comparison to the affected men and 72 cognitively normal age-matched subjects. The levels were independent of variables in education, apolipoprotein E genotype, cholesterol, and creatinine plasma concentrations, as well as hemoglobin content. CONCLUSIONS: The elevation of Abeta42 plasma levels in women with MCI may represent a biologic explanation for the sex-dependent increased incidence of late-onset AD in women identified by epidemiologic studies.

No evidence of association between CAG expansions and essential tremor in a large cohort of Italian patients.

Essential tremor (ET) is one of the most common movement disorders. However the pathogenesis is as yet unknown, although a genetic cause has long been recognised. Clinical and molecular evidences suggested that the ET gene might contain a CAG expanded region. In a cohort of Italian ET patients Repeat Expansion Detection (RED) approach did not demonstrate large CAG expansions. We extended the study towards specific targets: the channel proteins hSKCa3 and CACNL1A4. Direct assessment of CAG stretches within these two genes did not demonstrate any CAG expansion in affected subjects. Also a case-control analysis failed to reveal any evidence of association, thus excluding these genes as a cause of ET.

Clinical and genetic study of essential tremor in the Italian population.

Essential tremor (ET) is one of the most common movement disorders. The pathogenesis is as yet unknown, although a genetic cause has long been recognised. Clinical and molecular evidence suggested that the ET gene contains a CAG expanded region. We examined a cohort of 240 Italian ET patients, classified as familial (193 cases) and sporadic (47 cases). The clinical manifestations of ET patients confirmed that the disorder is characterised by a large phenotypic variability. Repeat expansion detection (RED) approach did not demonstrate large CAG expansions. Six families were genotyped with 12 microsatellites markers of 2p and 3q regions and analysed according to parametrical methods. Lod scores values obtained in these families excluded the association of ET with 2p and 3q loci. Our findings confirm the presence of genetic heterogeneity and suggest that at least a third locus is involved in the pathogenesis of familial essential tremor.