Italian consensus recommendations for a biomarker-based aetiological diagnosis in mild cognitive impairment patients.

BACKGROUND AND PURPOSE: Biomarkers support the aetiological diagnosis of neurocognitive disorders in vivo. Incomplete evidence is available to drive clinical decisions; available diagnostic algorithms are generic and not very helpful in clinical practice. The aim was to develop a biomarker-based diagnostic algorithm for mild cognitive impairment patients, leveraging on knowledge from recognized national experts. METHODS: With a Delphi procedure, experienced clinicians making variable use of biomarkers in clinical practice and representing five Italian scientific societies (neurology - Società Italiana di Neurologia per le Demenze; neuroradiology - Associazione Italiana di Neuroradiologia; biochemistry - Società Italiana di Biochimica Clinica; psychogeriatrics - Associazione Italiana di Psicogeriatria; nuclear medicine - Associazione Italiana di Medicina Nucleare) defined the theoretical framework, relevant literature, the diagnostic issues to be addressed and the diagnostic algorithm. An N-1 majority defined consensus achievement. RESULTS: The panellists chose the 2011 National Institute on Aging and Alzheimer's Association diagnostic criteria as the reference theoretical framework and defined the algorithm in seven Delphi rounds. The algorithm includes baseline clinical and cognitive assessment, blood examination, and magnetic resonance imaging with exclusionary and inclusionary roles; dopamine transporter single-photon emission computed tomography (if no/unclear parkinsonism) or metaiodobenzylguanidine cardiac scintigraphy for suspected dementia with Lewy bodies with clear parkinsonism (round VII, votes (yes-no-abstained): 3-1-1); 18 F-fluorodeoxyglucose positron emission tomography for suspected frontotemporal lobar degeneration and low diagnostic confidence of Alzheimer's disease (round VII, 4-0-1); cerebrospinal fluid for suspected Alzheimer's disease (round IV, 4-1-0); and amyloid positron emission tomography if cerebrospinal fluid was not possible/accepted (round V, 4-1-0) or inconclusive (round VI, 5-0-0). CONCLUSIONS: These consensus recommendations can guide clinicians in the biomarker-based aetiological diagnosis of mild cognitive impairment, whilst guidelines cannot be defined with evidence-to-decision procedures due to incomplete evidence.

The Italian dementia with Lewy bodies study group (DLB-SINdem): toward a standardization of clinical procedures and multicenter cohort studies design.

Dementia with Lewy bodies (DLB) causes elevated outlays for the National Health Systems due to high institutionalization rate and patients' reduced quality of life and high mortality. Furthermore, DLB is often misdiagnosed as Alzheimer's disease. These data motivate harmonized multicenter longitudinal cohort studies to improve clinical management and therapy monitoring. The Italian DLB study group of the Italian Neurological Society for dementia (SINdem) developed and emailed a semi-structured questionnaire to 572 national dementia centers (from primary to tertiary) to prepare an Italian large longitudinal cohort. The questionnaire surveyed: (1) prevalence and incidence of DLB; (2) clinical assessment; (3) relevance and availability of diagnostic tools; (4) pharmacological management of cognitive, motor, and behavioural disturbances; (5) causes of hospitalization, with specific focus on delirium and its treatment. Overall, 135 centers (23.6 %) contributed to the survey. Overall, 5624 patients with DLB are currently followed by the 135 centers in a year (2042 of them are new patients). The percentage of DLB patients was lower (27 ± 8 %) than that of Alzheimer's disease and frontotemporal dementia (56 ± 27 %) patients. The majority of the centers (91 %) considered the clinical and neuropsychological assessments as the most relevant procedure for a DLB diagnosis. Nonetheless, most of the centers has availability of magnetic resonance imaging (MRI; 95 %), electroencephalography (EEG; 93 %), and FP-CIT single photon emission-computerized tomography (SPECT; 75 %) scan for clinical applications. It will be, therefore, possible to recruit a large harmonized Italian cohort of DLB patients for future cross-sectional and longitudinal multicenter studies.

Ethical issues in end of life treatments for patients with dementia.

Dementia is a terminal disease, associated with great suffering and difficult decisions in the severe stage. The decision-making process is characterized by uncertainty because of lack of scientific evidence in treatments and by the need to reconcile conflicting points of view. In intercurrent diseases, aggressive interventions are used without consideration of its futility; in comparison with cancer, several consequences of physicians' attitude not to consider dementia as a terminal disease have been reported, especially concerning pain relief. Lack of evidence of artificial nutrition and hydration effectiveness makes advance care planning relevant.

Nicotinic receptor losses in dementia with Lewy bodies: comparisons with Alzheimer's disease.

We sought to delineate differences between alpha7 nicotinic acetylcholine receptor (nAChR) levels in Alzheimer's disease (AD), dementia with Lewy bodies (DLB) and age matched controls, as well as the correlations between alpha7 or non-alpha7 nAChR levels and synaptophysin (Syn) or choline acetyltransferase (ChAT) in DLB. Mean bungarotoxin (Bgt) binding was 2.7 - 1.1 for controls, 2.4 +/- 1.0 for AD and 1.4 +/- 0.5 for DLB. There were significant decreases in Bgt binding for the DLB group compared to either controls or AD. Mean epibatidine (Epi) binding was 14.8 +/- 3.2 for controls, 6.3 +/- 3.2 for AD and 7.1 +/- 2.4 fmoles/mg protein for DLB. Epi binding in both the AD and DLB groups was significantly lower than in the controls. Although Syn loss correlated with the decrease in Epi binding in both diseases, declining ChAT levels correlated with Epi binding only in DLB. These data demonstrate a different pattern of nAChR loss in AD and DLB that may, in part, explain some of the differences in the two phenotypes.

Diagnostic accuracy of dementia with Lewy bodies.

BACKGROUND: Diagnostic criteria for dementia with Lewy bodies (DLB) are still evolving. No data exist on prospective differentiation of DLB and Alzheimer disease (AD). OBJECTIVE: To examine the clinician's diagnostic accuracy for DLB and analyze factors contributing to false-positive DLB diagnoses. METHODS: A prospective series of 10 patients with clinically diagnosed DLB who came to autopsy was compared with 32 autopsy-confirmed cases of DLB (27 Lewy body variant, 5 diffuse Lewy body disease) and 20 autopsy-confirmed cases of AD (matched on age, sex, education, and initial Mini-Mental State Examination score) with regard to distinguishing and/or confounding clinical features. RESULTS: The clinical diagnostic accuracy for DLB was 50%, with 5 of the 10 patients clinically presumed to have DLB confirmed at autopsy. Of the 5 misdiagnosed cases, 4 had AD and 1 had progressive supranuclear palsy. The misdiagnosed DLB cases who had pure AD had fewer hallucinations (25%) than those with Lewy body variant (63%) or diffuse Lewy body disease (100%) (P = .048); however, an equal amount of spontaneous (in the absence of neuroleptics) extrapyramidal signs was found. There were no differences among groups with regard to daily fluctuations in cognition or falls. Compared with the AD control group, the misdiagnosed DLB cases with pure AD showed significantly more spontaneous extrapyramidal signs (P< or =.02). CONCLUSIONS: The clinician's diagnostic accuracy for DLB was poor. Early spontaneous extrapyramidal signs in AD were associated with false-positive clinical diagnoses of DLB. The distinction between DLB and AD may be improved by greater emphasis on hallucinations.

Neurochemical markers do not correlate with cognitive decline in the Lewy body variant of Alzheimer disease.

BACKGROUND: Reductions in neocortical synapses and cholinergic function occur in patients with Alzheimer disease (AD) and in patients with the Lewy body variant of AD (LBV). The relation between these losses and cognitive decline has been reported frequently in patients with AD but remains unclear for patients with LBV. OBJECTIVES: To investigate the relation between clinical markers of disease progression and choline acetyltransferase activity or synaptic density, measured by synaptophysin (Syn) level, in patients with LBV, and to investigate the relation of these neurochemical markers with one another. METHODS: Brain specimens of 41 patients with autopsy-confirmed (National Institute on Aging criteria for AD) LBV were examined. The last Mini-Mental State Examination and Blessed Information-Memory-Concentration test scores before death were reviewed. Midfrontal synapse counts were quantified by a dot-immunobinding assay for Syn. Choline acetyltransferase activity of the midfrontal cortex was assayed by established protocols. RESULTS: The last Mini-Mental State Examination score before death did not correlate significantly with Syn level (n = 25, r = 0.25, P = .24); however, there was a trend toward significance for the relation between last Mini-Mental State Examination score and choline acetyltransferase activity (n = 39, r = 0.31, P = .05). The last Blessed Information-Memory-Concentration test score did not correlate with either Syn level (n = 24, r = -0.17, P = .44) or choline acetyltransferase activity (n = 39, r = -0.16, P = .33). Finally, there was only a modest correlation between Syn level and choline acetyltransferase activity (n = 25, r = 0.38, P = .06), which did not reach statistical significance. CONCLUSION: Unlike AD, neurochemical markers do not appear to correlate well with cognitive decline in LBV.

The decline in synapses and cholinergic activity is asynchronous in Alzheimer's disease.

OBJECTIVE: To determine the timing of cholinergic loss and reduction of synapses in AD. BACKGROUND: Decrements in neocortical synapses and cholinergic function occur in AD and correlate with cognitive decline. However, how early in the disease process these changes appear remains unclear. METHODS: An autopsy series of 89 demented patients with pathologically confirmed AD (National Institute on Aging and Consortium to Establish a Registry for Alzheimer's Disease criteria) and 18 normal control subjects (NC). The AD cases were stratified according to their last Mini-Mental State Examination (MMSE) score prior to death as mild (MMSE = 20; n = 14), moderate (MMSE = 10 to 19; n = 20), severe (MMSE = 1 to 9; n = 29), and very severe (MMSE = 0; n = 26). Midfrontal (MF) synapse density was assessed by dot-immunobinding assay for synaptophysin (Syn), and MF choline acetyltransferase (ChAT) activity was determined using standard protocols. RESULTS: Compared with those in NC, neither Syn nor ChAT was appreciably reduced in patients with mild AD at death. Decline of ChAT was significant only in AD patients who died in the late stages of the disease and was maximal in those who had more severely deteriorated. In contrast, decline of Syn was significant and almost maximal in patients in intermediate or moderate stages. Consequently, the last MMSE score prior to death correlated more strongly with ChAT than Syn when the AD cohort included more impaired patients (r = 0.46 versus 0.40). The reverse occurred when only less impaired patients (MMSE = 10) were included in the analyses (r = 0.28 versus 0.64). There was only a modest correlation between Syn and ChAT activity. CONCLUSIONS: The results imply an asynchronous pattern of decline of synapses and cholinergic activity, with Syn loss preceding ChAT decrements. However, neither MF synapse reduction nor cholinergic dysfunction appears to be an early event in AD.

Long-term acetyl-L-carnitine treatment in Alzheimer's disease.

In a double-blind, placebo-controlled, parallel-group, randomized clinical trial, we studied the efficacy of long-term (1-year) oral treatment with acetyl-L-carnitine in 130 patients with a clinical diagnosis of Alzheimer's disease. We employed 14 outcome measures to assess functional and cognitive impairment. After 1 year, both the treated and placebo groups worsened, but the treated group showed a slower rate of deterioration in 13 of the 14 outcome measures, reaching statistical significance for the Blessed Dementia Scale, logical intelligence, ideomotor and buccofacial apraxia, and selective attention. Adjusting for initial scores with analysis of covariance, the treated group showed better scores on all outcome measures, reaching statistical significance for the Blessed Dementia Scale, logical intelligence, verbal critical abilities, long-term verbal memory, and selective attention. The analysis for patients with good treatment compliance showed a greater drug benefit than for the overall sample. Reported adverse events were relatively mild, and there was no significant difference between the treated and placebo groups either in incidence or severity.

E4 allele dosage does not predict cholinergic activity or synapse loss in Alzheimer's disease.

OBJECTIVE: To investigate the relationship between apolipoprotein E (APOE) genotype and both cholinergic dysfunction and synapse loss in AD. BACKGROUND: A reduction in neocortical synapses and marked losses in the cholinergic system occur in AD. It has been suggested that the number of APOE epsilon4 alleles is inversely related to choline acetyltransferase (ChAT) activity, thereby influencing cholinergic function. Whether APOE genotype may influence neocortical synapse loss remains unclear. METHODS: An autopsy series of 182 patients with AD (National Institute on Aging and Consortium to Establish a Registry for Alzheimer's Disease criteria) and 16 normal controls (NC). APOE genotype was determined in blood samples or in postmortem brain tissue. Midfrontal synapse counts (AU/microg) were quantified by a dot-immunobinding assay for synaptophysin (Syn). Midfrontal ChAT activity (nmol/h/100 mg) was assessed using standard assays. RESULTS: Mean midfrontal ChAT activity and Syn were both significantly reduced in patients with AD compared with NC. The relationship between ChAT activity and number of epsilon4 allele copies in AD was complex, with ChAT activity lower in patients with either two or no epsilon4 alleles compared with those with one epsilon4 allele. There was no relationship between APOE genotype and synapse loss in AD. Syn density was almost identical across the three genotypes. CONCLUSIONS: Unlike other studies, we failed to detect a linear relationship between ChAT activity and number of epsilon4 allele copies in the midfrontal cortex of this large sample of patients with AD. Our data also show that the presence of epsilon4 allele does not influence midfrontal synapse loss in AD. This suggests that factors other than APOE genotype may be operative in the decline in midfrontal cholinergic function and synapses seen in AD.

Cholinergic dysfunction in diseases with Lewy bodies.

OBJECTIVE: To evaluate cholinergic activity in diseases with Lewy bodies (LB; LB variant of AD [LBV], diffuse LB disease [DLBD], and Parkinson's disease [PD]) to determine if 1) AD changes are requisite to cholinergic dysfunction, 2) cholinergic activity declines to the same extent in neocortical and archicortical areas, and 3) cholinergic loss is influenced by APOE genotype. BACKGROUND: Like AD, diseases with LB are associated with decreased choline acetyltransferase (ChAT) activity. Increased APOE epsilon4 allele frequency has been reported in LBV. Whether APOE genotype affects cholinergic function in LBV remains unclear. METHODS: An autopsy series of 182 AD (National Institute on Aging and Consortium to Establish a Registry for Alzheimer's Disease criteria), 49 LBV, 11 PD, 6 DLBD, and 16 normal control (NC) subjects. APOE genotype and ChAT activity (nmol/h/100 mg) in the midfrontal and hippocampal cortices were determined. RESULTS: Mean midfrontal ChAT activity was markedly reduced in diseases with LB (LBV: 53.3 +/- 39.0; PD: 54.8 +/- 35.7; DLBD: 41.3 +/- 24.8) compared to NC (255.4 +/- 134.6; p < 0.001) and AD (122.6 +/- 78.9; p < 0.05). Among diseases with LB, midfrontal ChAT activity was decreased to a similar extent in patients with (LBV) and without (DLBD and PD) AD pathology. Although mean ChAT activity for LBV was less than half that for AD in the midfrontal cortex, it was similar to that for AD in the hippocampus (LBV: 243.5 +/- 189.7; AD: 322.8 +/- 265.6; p > 0.05). However, hippocampal ChAT activity for both AD and LBV was lower than that for NC (666.5 +/- 360.3; p < 0.001). The epsilon4 allele dosage did not influence midfrontal ChAT activity in LBV. CONCLUSION: Marked losses in midfrontal ChAT activity occur in diseases with LB, independent of coexistent AD changes. A greater midfrontal, as opposed to hippocampal, cholinergic deficit may differentiate LBV from AD. The lack of a relationship between epsilon4 allele dosage and midfrontal ChAT activity suggests that other factors may play a role in its decline in LBV.

Rate of progression and prognostic factors in Alzheimer's disease: a prospective study.

OBJECTIVE: To study rate of progression and correlates of cognitive and functional/behavioral deterioration in Alzheimer patients. DESIGN: A 1-year multicenter prospective study. SETTING: Outpatients and inpatients at geriatric institutions. PATIENTS: Fifty-six patients with a clinical diagnosis of Alzheimer's disease according to DSM-III criteria of Primary Degenerative Dementia. MAIN OUTCOME MEASURES: Blessed Dementia Scale (BDS) and Blessed Information-Memory-Concentration test (BIMC) measured at baseline, third, sixth, and twelfth month. RESULTS: The mean annual (+/- SD) rate of progression of our sample was 3.5 (+/- 3.7) points on the BDS and 2.6 (+/- 4.9) on the BIMC, with a wide range of variability. The level of cognitive impairment (BIMC score) at baseline predicted functional and behavioral deterioration: the better the initial BIMC score, the less the rate of negative change of BDS (r = 0.37, P = 0.006). Furthermore, the younger the patients at the disease onset, the faster the progression of cognitive impairment (r = 0.48, P = 0.0003), with men having a slower rate of progression (P = 0.004) than women. CONCLUSIONS: The present study confirms previous findings showing a wide individual variability in rate of progression of cognitive and functional/behavioral impairment as assessed by BIMC and BDS. The cognitive profile may predict the clinical evolution better than the functional and behavioral status, with patients with an earlier onset and women having a faster deterioration.

Single-dose safety and pharmacokinetics of a potential cognition-enhancing compound, CL 275,838, in healthy volunteers.

The pharmacokinetics and safety of CL 275,838, a potential cognition-enhancing compound, were studied after single escalating oral doses first in young healthy male volunteers and then in old (60-74 years) and very old (over 75 years) volunteers of both sexes. In all age groups absorption of CL 275,838 was rapid as assessed by the mean time to reach maximum plasma concentrations (Cmax) which averaged 1-2 hr, regardless of the dose administered. In young male volunteers both Cmax and area under the curve (AUC) increased proportionally with dose from 10 to 100 mg. Mean elimination half-lives (t1/2) of the parent compound (18-21 hr) and of its circulating metabolites II (20-22 hr) and IV (27-30 hr) were well comparable for the doses tested (50 and 100 mg). Age did not appreciably affect plasma Cmax of CL 275,838 or its two metabolites. Mean AUC and elimination half-life did not appreciably differ between old and very old subjects given 50 mg CL 275,838, with the limitations dictated by the small number of elderly subjects examined. Compared with younger volunteers receiving comparable doses, however, the elderly had higher mean plasma AUC of the unchanged compound and its two metabolites, although the parameter varied widely between subjects. The mean elimination t1/2 (+/- SD) was longer in the elderly (38.8 +/- 19.6, 50.5 +/- 24.5 and 41.7 +/- 12.1 hr, respectively, for the parent compound and its metabolites II and IV) than in the young subjects. The cause(s) of these variations and the possible clinical implications remain to be established.(ABSTRACT TRUNCATED AT 250 WORDS)

Multiple-dose pharmacokinetics and safety of a potential memory-enhancing compound, CL 275,838, in healthy male volunteers.

The pharmacokinetics and safety of CL 275,838, a new potential memory-enhancing compound, were examined after 14 daily doses (50 and 100 mg) in 16 healthy male volunteers, age 20 to 59 years, in a randomized, double-blind, placebo-controlled, parallel group study. Trough blood samples (predose) were collected on days 2, 4, 7, 10, and 14, and further samples were drawn after the final dose (day 14) to define the multiple-dose kinetics of the parent compound and its metabolites II and IV. Intercurrent clinical events, vital functions, EEG, ECG, and cognitive tests (attention, verbal memory, and spatial memory) were considered as outcome measures of safety. Performance in cognitive tests was also studied to collect preliminary information on possible therapeutic action. Predose plasma concentrations of the parent compound and its two metabolites increased approximately in proportion to the dose, and accumulation was complete within 7 days, regardless of the dose. At steady state, mean Cmax and AUC of the parent compound and its two metabolites were dose related. Mean wash-out t1/2 was 18 to 20 hours for the parent compound, 22-23 hours for metabolite II, and 28-33 hours for metabolite IV; these elimination t1/2 are comparable for the two doses, and are similar to those observed in single-dose studies. For the 50-mg-dose group, predicted and observed average plasma concentrations (Css) of CL 275,838 and its two metabolites did not differ significantly.(ABSTRACT TRUNCATED AT 250 WORDS)

[Diagnostic problems in spontaneous bacterial peritonitis]. / La problematica diagnostica nella peritonite batterica spontanea.

In spontaneous bacterial peritonitis (SBP) the ascitic fluid culture (certain criterion of diagnosis) may be negative despite an evident clinical and biochemical picture. Therefore the diagnosis may be sometimes more "probable" than "certain". The authors performed a comparative analytical study--from a clinical, biochemical and prognostic point of view--between a group of 10 "probable" SBP (10 cirrhotic pts.) and 9 "certain" SBP (9 cirrhotic pts.). 115 "normal ascitic fluids" (negative culture in absence of any SBP-symptoms), collected from 82 cirrhotic pts., were used as control group. The ascitic concentration of white blood cells (WBC)/mmc and polymorphonuclear cells (PMN)/mmc was significantly different between the SBP and control group (p less than 0.001) and between the "certain" and "probable" SBP (p less than 0.02). The latter have a mean WBC and PMN/mmc count that is lower than the "certain" SBP and on the contrary a significantly higher ascitic glucose content (p less than 0.05). Probably that means a lower ascitic bacterial inoculum, which is below the threshold of detectability by current culture techniques. Serum laboratory tests showed no differences between the "probable" and the "certain" SBP groups, although, however they were worse than the control group. The symptoms and the prognosis resulted nearly the same in both groups. In spite of a high rate of recovery (57.9%) the global survival at the follow-up (10 +/- 5.2 months, range 6-19) was only 26.3%. The wide clinical, biochemical and prognostic overlap of the two groups leads us to consider as "certain" all the cases of "probable" SBP. Owing to the fact that only an early recognition and therapy are known to affect the prognosis significantly, the obvious conclusion is that in the SBP the suspicion is more important that the diagnostic certainty. Furthermore--in agreement with previous studies--the cutoff limit of 250 PMN/mmc has shown the best statistical diagnostic value for a rapid diagnosis (sensibility 100%, diagnostic accuracy 92.5%, negative predictive value 100%, likelihood ratio 1.9).

Intra-arterial or intravenous thrombolysis for acute ischemic stroke? The SYNTHESIS pilot trial.

OBJECTIVE To assess the feasibility, safety and preliminary efficacy of intra-arterial thrombolysis (IAT) compared with standard intravenous thrombolysis (IVT) for acute ischemic stroke. METHODS Eligible patients with ischemic stroke, who were devoid of contraindications, started IVT within 3 h or IAT as soon as possible within 6 h. Patients were randomized within 3 h of onset to receive either intravenous alteplase, in accordance with the current European labeling, or up to 0.9 mg/kg intra-arterial alteplase (maximum 90 mg), over 60 min into the thrombus, if necessary with mechanical clot disruption and/or retrieval. The purpose of the study was to determine the proportion of favorable outcome at 90 days. Safety endpoints included symptomatic intracranial hemorrhage (SICH), death and other serious adverse events. RESULTS 54 patients (25 IAT) were enrolled. Median time from stroke onset to start to treatment was 3 h 15 min for IAT and 2 h 35 min for IVT (p<0.001). Almost twice as many patients on IAT as those on IVT survived without residual disability (12/25 vs 8/29; OR 3.2; 95% CI 0.9 to 11.4; p=0.067). SICH occurred in 2/25 patients on IAT and in 4/29 on IVT (OR 0.5; CI 0.1 to 3.3; p=0.675). Mortality at day 7 was 5/25 (IAT) compared with 4/29 (IVT) (OR 1.6; CI 0.4 to 6.7; p=0.718). There was no significant difference in the rate of other serious adverse events. CONCLUSIONS Rapid initiation of IAT is a safe and feasible alternative to IVT in acute ischemic stroke.

Ethical questions in the treatment of subjects with dementia. Part I. Respecting autonomy: awareness, competence and behavioural disorders.

The document deals with some ethical issues raised by the treatment of demented people. In particular the conceptual and empirical aspects of the assessment of awareness and competence of these patients are analysed, as well as the dilemmas related to the treatment of behavioral disorders.

Pergolide effect on cognitive functions in early-mild Parkinson's disease.

In the present study, we evaluated the effect of pergolide, a mixed D1/D2 agonist, on cognitive function in mild Parkinson's disease (PD). After a two-week wash-out phase, twenty patients with a Hoehn and Yahr score

Smoking affects the phenotype of Alzheimer disease.

Because epidemiologic and in vitro evidence conflict, the authors studied the association between smoking and Alzheimer disease (AD) in 46 never, 47 former, and 15 active smokers with AD followed to autopsy. Disease parameters were examined by smoking status and amount smoked in bivariate tests and in multivariate models controlling for age, sex, education, and APOE status. Smoking status was not associated with cognitive or neuropathologic measures. However, active smokers were significantly younger at death and higher levels of smoking were associated with shorter disease duration.

Atypical features and prognosis of Wallenberg syndrome: longitudinal study.

The lessons of a retrospective study of 24 consecutive cases of Wallenberg syndrome observed during a 6-year span are described: the high frequency of signs and symptoms not considered typical, such as headache, diplopia, supranuclear homolateral facial paresis and homolateral brachiocrural hemiparesis; the unfavorable short term course in a high percentage of cases, and the risk of sudden respiratory arrest.

The importance of neuritic plaques and tangles to the development and evolution of AD.

OBJECTIVE: To determine the relation of neuritic plaques (NPs) and neurofibrillary tangles (NFTs) to the development and evolution of Alzheimer disease (AD). METHODS: An autopsy series of 102 patients with dementia and pathologically confirmed AD and 29 normal control subjects (NCs) was studied. AD cases were stratified according to their last Mini-Mental State Examination (MMSE) before death as mild, moderate, severe, or very severe. NPs and NFTs were enumerated in the midfrontal (MF), inferior parietal (IP), superior temporal (ST), hippocampal (Hip), or entorhinal cortices using thioflavin-S preparations. RESULTS: Most (87%) of the NCs had allocortical NFTs, whereas only a minority (37%) displayed neocortical NPs, and even fewer (19%) showed Hip NPs. In contrast, none of the NCs exhibited neocortical NFTs, except one case with a single ST tangle. However, neocortical NFTs were not detected in even 10% of the patients with AD and, in particular, were absent in nearly 50% of those with mild disease at death. Thus, their sensitivity as a marker of AD was lower than that of NPs, which, conversely, were found in all patients with AD. Comparing NCs and patients with mild AD, significant differences were found for numbers of NPs only. Across the AD groups, in contrast, although NP and NFT density increased with dementia severity, significant differences consistently emerged for NFTs alone. CONCLUSIONS: Deterioration in Alzheimer disease appears to be driven by neuritic plaques and neurofibrillary tangles at different stages of the disease. The significant increase in neuritic plaques, but not neurofibrillary tangles, in patients with even mild Alzheimer disease at death compared with normal control subjects suggests that only neuritic plaques are associated with the earliest symptoms of Alzheimer disease.