Cognitive deficit, and neuropathological correlates, in the oldest-old.

Several disorders are usually involved in the cognitive deficit of the oldest old. Alzheimer disease is the commonest. It is usually characterized by progressive memory impairment - neocortical symptoms occurring much later in the course of the disease. Alzheimer disease should not be considered any more as the single cause of a cognitive deficit in a very old patient. Vascular alterations, possibly causing microinfarcts, are commonly associated, especially in cerebral amyloid angiopathy. A slowly progressive memory deficit with negative CSF biomarkers of Alzheimer's disease may be due to hippocampal sclerosis that may be the consequence of multiple causes: in most of the cases, it is associated with neuronal TDP-43 inclusions. Recently, a distribution of these inclusions to a territory more extensive than the hippocampus has been reported and attributed to a new entity, called Limbic-predominant Age-related TDP-43 Encephalopathy (LATE) with or without hippocampal sclerosis. The presence of cortical Lewy bodies may cause an intellectual deficit or contribute to it. The prevalence of dementia with cortical Lewy bodies in the oldest old is discussed. Tau inclusions in cortical glia have also been shown to participate to the intellectual deficit. Association of neurodegenerative and vascular changes is the most frequent situation in the very old patients. Systemic diseases such as diabetes or heart failure, prescription drugs (when misused), or toxic such as alcohol may also contribute to the cognitive impairment and be amenable to treatment.

GREFON recommendations for assessment of instrumental activities of daily living in memory clinics.

Following a review of the available assessment scales and current practices of evaluation of instrumental activities of daily living (IADL) in French memory centres by GREFON (Groupe de réflexion sur l'évaluation fonctionnelle; Working Group on Functional Assessment), the main aim of this position paper was to provide good clinical practice (GCP) guidelines for the assessment of IADL. Another aim was to highlight the need for innovative tools adapted to the present and future evolution of such activities in real life, including the use of new technologies, the need for earlier detection of IADL impairment during the diagnostic process of mild neurocognitive disorders, and greater sensitivity to IADL changes during follow-up to allow adaptation of clinical management and evaluation of the impact of therapeutic interventions.

Association between Vitamin D Deficiency and Prognosis after Hip Fracture Surgery in Older Patients in a Dedicated Orthogeriatric Care Pathway.

OBJECTIVES: Vitamin D deficiency is common in patients undergoing hip fracture surgery (HFS) and has been found to be associated with poor post-operative outcome in other settings. This study aimed to analyze the association between vitamin D status and prognosis after HFS. DESIGN: Observational, prospective, single-center study. SETTING AND PARTICIPANTS: All patients admitted in a peri-operative geriatric unit between 2009 and 2020 for HFS were included. MEASUREMENTS: A moderate vitamin D deficiency was defined by a vitamin D level between 25 and 75 nmol/l and a severe deficiency by a vitamin D level <25 nmol/l. Primary endpoint was mortality 6 months after surgery. Secondary endpoints were bacterial infections and delirium during hospitalization. Odds ratio (OR) and 95% confidence interval (95%CI) were computed using logistic regression models with adjustment for confounders. RESULTS: 1197 patients were included (median age 87 years, IQR [82-91]). Median vitamin D level was 55 nmol/l (IQR [30-75 nmol/l]). Moderate and severe vitamin D deficiencies were reported in 53% and 21% of patients, respectively. There was no significant association between moderate or severe vitamin D deficiencies and 6-month mortality (OR 0.91, 95%CI [0.59-1.39], and OR 1.31, 95%CI [0.77-2.22], respectively), bacterial infection (OR 0.89, 95%CI [0.60-1.31] and OR 1.55, 95%CI [0.99-2.41], respectively), nor delirium (OR 1.03, 95%CI [0.75-1.40], and OR 1.05, 95%CI [0.70-1.57], respectively). CONCLUSION: Vitamin D deficiency was not associated with mortality, bacterial infection or delirium after HFS. Our results suggest that comorbidities, functional status and post-operative complications are the main determinants of post-operative outcome after HFS.

Sleep disorders and their impacts on healthy, dependent, and frail older adults.

BACKGROUND: Sleep disorders differ widely in the heterogeneous older adult population. Older adults can be classified into three groups based upon their overall level of disability: healthy, dependent, and frail. Frailty is an emerging concept that denotes older persons at increased risk for poor outcomes. OBJECTIVE: The aim of this consensus review is to describe the sleep disorders observed in healthy and dependent older adults and to discuss the potential sleep disorders associated with frailty as well as their potential consequences on this weakened population. METHODS: A review task force was created including neurologists, geriatricians, sleep specialists and geriatric psychiatrists to discuss age related sleep disorders depending on the three categories of older adults. All published studies on sleep in older adults on Ovid Medline were reviewed and 106 articles were selected for the purpose of this consensus. RESULTS: Many healthy older adults have complains about their sleep such as waking not rested and too early, trouble falling asleep, daytime napping, and multiple nocturnal awakenings. Sleep architecture is modified by age with an increased percentage of time spent in stage one and a decreased percentage spent in stages three and four. Insomnia is frequent and its mechanisms include painful medical conditions, psychological distress, loss of physical activity and iatrogenic influences. Treatments are also involved in older adults' somnolence. The prevalence of primary sleep disorders such as restless legs syndrome, periodic limb movements and sleep disordered breathing increases with age. Potential outcomes relevant to these sleep disorders in old age include mortality, cardiovascular and neurobehavioral co-morbidities. Sleep in dependent older adults such as patients with Alzheimer Disease (AD) is disturbed. The sleep patterns observed in these patients are often similar to those observed in non-demented elderly but alterations are more severe. Nocturnal sleep disruption and daytime sleepiness are the main problems. They are the results of Sleep/wake circadian rhythm disorders, environmental, psychological and iatrogenic factors. They are worsened by other sleep disorders such as sleep disordered breathing. Sleep in frail older adults per se has not yet been formally studied but four axes of investigation should be considered: i) sleep architecture abnormalities, ii) insomnia iii) restless legs syndrome (RLS), iv) sleep disordered breathing. CONCLUSION: Our knowledge in the field of sleep disorders in older adults has increased in recent years, yet some groups within this heterogeneous population, such as frail older adults, remain to be more thoroughly studied and characterized.

[Specificity of epileptic seizures in the elderly: A proposed electro-clinical scale]. / Spécificités des crises d'épilepsie chez le sujet âgé : proposition d'un score électro-radioclinique d'orientation.

Diagnosis of epileptic seizure may be difficult in older patients because seizure manifestations are often unusual: confusion, paresis... and because there are multiple differential diagnoses (syncope, transient ischemic attack, transient global amnesia...). To promote and facilitate the diagnosis of seizures in the elderly, neurologists and gerontologists must work together and focus their strategy on two points: firstly, the knowledge of the specific presentation of seizures in elderly patients, and secondly, the adoption of a reasoning based on seizures and not epileptic syndromes. A multidisciplinary group worked on epilepsy of the elderly to elaborate an electro-clinical score which aims to help establish the diagnosis of epilepsy in elderly patients in different clinical settings. This electro-clinical score is based on a systematic review of scientific literature and the recommendations are explicitly linked to supporting evidence. Further, clinical validation of the electro-clinical score is required.

[Effects of hypomagnesemia]. / Les effets de l'hypomagnésémie.

INTRODUCTION: The clinical consequences of plasmatic magnesium variations are underecognized in clinical practice. The dosage of plasmatic magnesium is underused and not reliable. Moreover, hypomagnesemia is often associated with other metabolic disorders (hypocalcemia, hypokaliemia), which are responsible for several symptoms. CASE REPORT: We report an 85-year-old man who presented with repeated bronchospasm, confusion, and abdominal and muscular pain, attributed to low magnesium serum level. We then review pathophysiology, various etiologies, clinical features, diagnostic challenge and treatment of low magnesium serum level. CONCLUSION: Hypomagnesemia is poorly known and diagnosed. Therapeutic issues have not been clearly defined.

[Transfusion in elderly patients]. / Transfusion chez les patients âgés.

The frequency of anemia is responsible of a frequent use of transfusion in elderly patients. However, transfusion in elderly patients requires several warnings. First, semiology of elderly patients is characterized with atypical clinical signs, and anemia tolerance is often difficult to appreciate. Second, numerous comorbidities make of elderly patients an heterogeneous population, in which guidelines are poorly applicable. Last, elderly patients are particularly sensitive to iatrogenic events, and the haemodynamic overload related to transfusion has to be carefully managed. All these difficulties raise the need of prospective studies on transfusion in elderly patients to validate clinical practice.

Restoration of thiamine status with white or whole wheat bread in a thiamine-depleted rat model.

Long-term thiamine deficiency has been largely documented, whilst little is known about effects of short-term depletion/repletion periods on thiamine vitamers status. Rats were submitted to short-term depletion (8 days) followed by different durations of repletion (3 or 14 days) with thiamine from bread (whole wheat bread or white bread, whole B and white B respectively) or corresponding controls. Short-term depletion drastically decreased plasma thiamine (-97%) and its urinary excretion (-77%). TDP (thiamine diphosphate) was strongly affected in liver (-67%) but less affected in cerebellum (-38%) or kidneys (-45%). Short-term repletion (3 days) with whole B diet or its control restored TDP at initial values in cerebellum and kidneys. A longer repletion (14 days) was required to restore liver TDP. Comparison of the diet groups indicates that thiamine status in tissues of rat fed whole B or white B diet was comparable to that of rats fed purified thiamine. Plasma thiamine concentration could not be restored at initial values in the bread groups or respective controls. In conclusion, thiamine in whole wheat bread appears effective in preventing marginal deficiencies and plasma thiamine is a less reliable indicator of thiamine status than tissue TDP levels.

[Neurological manifestations of type 1 Gaucher's disease: Is a revision of disease classification needed?]. / Les manifestations neurologiques de la maladie de Gaucher de type 1: vers une remise en cause de la classification actuelle?

INTRODUCTION: Gaucher's disease (GD), the most prevalent inherited lysosomal storage disorder, is caused by deficient glucocerebrosidase activity. The resulting accumulation of glucocerebrosides in lysosomes of macrophages leads to hepatosplenomegaly, anemia, thrombocytopenia, and various bone manifestations. Gaucher's disease is classified into 3 types based on the nature of its effects on the central nervous system. Type 1, the most common variant, is classically nonneuronopathic. However, the occurrence of Parkinsonism seems to be more frequent in type I Gaucher's disease than in the general population. Furthermore, heterozygotes for certain glucocerebrosidase gene mutations have a higher risk to develop Parkinson's disease. OBSERVATIONS: We report our experience about 9 patients with Gaucher's disease and their association with neurological manifestations. CONCLUSION: These recent data may discuss Gaucher's classification and the existence of a continuum between neurologic and non-neurologic forms of the disease.

[Medical comorbidity in Alzheimer's disease: baseline characteristics of the REAL.FR Cohort]. / Comorbidités et maladie d'Alzheimer: données à l'inclusion de la cohorte gériatrique REAL.FR.

PURPOSE: Alzheimer's disease (AD) evolves over about ten years with cognitive decline that can be considered as linear. Comorbidities are frequent in geriatric population. The major objective of this study is to determine whether comorbidity influences natural history of AD. MATERIALS AND METHODS: This is a prospective, multicentric French study (REAL.FR) of a cohort of ambulatory patients suffering from AD from a mild to a moderately severe stage, with a Mini-Mental State between 10 and 26, and followed with a caregiver. We evaluated the comorbidities and they were quantified using the Charlson index. RESULTS: We analysed 579 AD patients enrolled between April 2000 and June 2002. Majority of patients were women (72%). Average age and MMS average score were respectively 77.4 +/- 7.1 and 20.1 +/- 4.5. Cardiovascular diseases were the most frequent comorbid conditions (34%), before sensorial handicap (23%), and neurological diseases (18%) apart from dementia. Four AD patients groups differed according to the comorbidities figures, from none to more than three (maximum 8). Average Charlson index was 1.5 +/- 0.9. CONCLUSION: The follow-up of the four AD patients groups, differentiated by the comorbidities figures, should allow to precise the influence of comorbidities on the AD evolution. Charlson index could be used to quantify the comorbidities in the cohort's follow-up. However, this index, validated in a cohort of cancer patients, show limits for its use in geriatric population.

Determination of thiamine and its phosphate esters in rat tissues analyzed as thiochromes on a RP-amide C16 column.

A new reversed-phase chromatographic method is described for the separation and quantification of thiamine (T), thiamine monophosphate (TMP) and diphosphate (TDP) in rat tissues. Sample extraction with perchloric acid (HClO(4)) was found more suitable than extraction with trichloroacetic acid (TCA), as regards convenience and background fluorescence. Derivatization of thiamine vitamers to thiochromes was optimized and complete separation of TDP and TMP thiochromes was obtained on a RP-amide C16 column in isocratic elution, with T thiochrome eluting in less than 10 min. The precision and the accuracy of the HPLC procedure were assessed: ranging from 0.5 to 7.7% for intra-day and from 2.0 to 9.4% for inter-day precision, a recovery average of 101% was determined (range 90-111%). Mean values of recovery for TDP, TMP or T were 91, 96 and 90% for liver extracts, respectively. Analysis of vitamers in tissues of rat submitted to 8 days thiamin deficiency, followed by a 14 days repletion, showed a significant reduction of TPP after 8 days of depletion in liver (-67%), brains (-50%), kidneys (-60%), followed by a complete recovery upon repletion.

[Behavioral and psychological symptoms in dementia: description and management]. / Les symptômes psychologiques et comportementaux de la démence: description et prise en charge.

Behavioral and Psychological Symptoms in Dementia (BPSD) are, beside cognitive disorders, major features of Alzheimer's disease and related disorders. Diagnosis is important to enhance our knowledge of the pathophysiology of dementia and of their functional consequences for patients and caregivers. Pharmacological and non-pharmacological management of dementia depends to a large extent on the presence of BPSD. A committee of geriatricians, neurologists and psychiatrists specialized in dementia (THEMA 2) has promoted an epidemiological, diagnostic and therapeutic update in this field. This work was based on the BPSD Consensus Conference Report edited in 2000 by the International Psychogeriatric Association. This report was updated with the most recent literature reports, and was adapted to the French environment. This paper is a synthesis of this meeting, validated and corrected by the entire Thema 2 group.

[Consensus statement on severe dementia]. / Consensus sur la démence de type Alzheimer au stade sévère.

Under the auspices of the French Society of Gerontology and Geriatrics, a multidisciplinary team including geriatritians, neurologists, epidemiologists, psychiatrists, pharmacologists and public health specialists developed a consensus on care for patients with severe dementia. They defined 21 recommendations for general practitioners, long-term care physicians and specialists based on knowledge available in 2005. At all stages of the disease, the objective of care is to improve as much as possible quality-of-life for the patient and his/her family, including a life project until the end of life. It is always possible to do something for these patients and their family: nutritional status, behavior disorders, and incapacities to deal with basic activities of daily life have to be taken in consideration. Resource allocation and proximity care have to be targeted. Research areas necessary to improve the care of patients with severe dementia has been selected.

[Consensus statement on severe dementia]. / Consensus sur la démence de type Alzheimer au stade sévère.

Under the auspices of the French Society of Gerontology and Geriatrics, a multidisciplinary group of experts, including geriatricians, neurologists, epidemiologists, psychiatrists, pharmacologists, and public health specialists developed consensus recommendations about care for patients with severe dementia. They defined 21 recommendations for general practitioners, long-term care physicians, and specialists, based on the knowledge currently available (2005). The aim of care at all stages is to mitigate the quality-of-life of patient, caregiver, and family insofar as possible, combining care and future planning until the end of life. Management, to take into account problems including nutritional status, behavior disorders, and ability (or inability) to perform activities of daily living, must be global, multidisciplinary, and coordinated and must optimize use of local medical and social resources. The group also stressed the importance of clinical research to improve knowledge of disease course and assess management strategies and recommended specific area for research.

Pharmacological therapy in progressive supranuclear palsy.

BACKGROUND: To our knowledge, previous reports on drug treatment in progressive supranuclear palsy have not evaluated autopsy-confirmed cases. OBJECTIVE: To evaluate pharmacological treatment responses from detailed clinical records in patients with autopsy-confirmed progressive supranuclear palsy. SUBJECTS AND METHODS: We reviewed medical records for clinical presentation and pharmacological response in 12 patients with autopsy-confirmed progressive supranuclear palsy diagnosed using the National Institute of Neurological Disorders and Stroke pathologic criteria. For each drug class, exposure, global positive response, and specific positive response (parkinsonism, other movement disorders, or gaze dysfunction) were recorded. RESULTS: Drug classes examined were dopaminergics (all patients), tricyclics (3 patients), methysergide maleate (3 patients), 5-hydroxytryptophan (2 patients), and anticholinergics and selective serotonin inhibitors (1 patient). Positive clinical response was detected in 7 of the patients receiving dopaminergic drugs and in 1 patient each receiving tricyclics, methysergide, and 5-hydroxytryptophan, respectively. None of the patients responded markedly however, and there was no persistent beneficial effect. Use of dopaminergic drugs most frequently improved parkinsonian features, but disabling adverse effects included orthostatic hypotension (6 patients), hallucinations and delusions (3 patients), gastrointestinal complaints (3 patients), and dizziness (1 patient). Only 1 patient developed dyskinesia. CONCLUSION: Use of antiparkinsonian medications and other neurotransmitter replacement therapies was largely ineffective and caused frequent adverse effects in this series of patients with autopsy-confirmed with progressive supranuclear palsy.

Progression of dysarthria and dysphagia in postmortem-confirmed parkinsonian disorders.

BACKGROUND: Dysarthria and dysphagia are known to occur in parkinsonian syndromes such as Parkinson disease (PD), dementia with Lewy bodies (DLB), corticobasal degeneration (CBD), multiple system atrophy (MSA), and progressive supranuclear palsy (PSP). Differences in the evolution of these symptoms have not been studied systematically in postmortem-confirmed cases. OBJECTIVE: To study differences in the evolution of dysarthria and dysphagia in postmortem-confirmed parkinsonian disorders. PATIENTS AND METHODS: Eighty-three pathologically confirmed cases (PD, n = 17; MSA, n = 15; DLB, n = 14; PSP, n = 24; and CBD, n = 13) formed the basis for a multicenter clinicopathological study organized by the National Institute of Neurological Disorders and Stroke, Bethesda, Md. Cases with enough clinicopathological documentation for the purpose of the study were selected from research and neuropathological files of 7 medical centers in 4 countries (Austria, France, England, and the United States). RESULTS: Median dysarthria latencies were short in PSP and MSA (24 months each), intermediate in CBD and DLB (40 and 42 months), and long in PD (84 months). Median dysphagia latencies were intermediate in PSP (42 months), DLB (43 months), CBD (64 months), and MSA (67 months), and long in PD (130 months). Dysarthria or dysphagia within 1 year of disease onset was a distinguishing feature for atypical parkinsonian disorders (APDs) (specificity, 100%) but failed to further distinguish among the APDs. Survival time after onset of a complaint of dysphagia was similar in PD, MSA, and PSP (15 to 24 months, P =.7) and latency to a complaint of dysphagia was highly correlated with total survival time (rho = 0.88; P<.001) in all disorders. CONCLUSIONS: Latency to onset of dysarthria and dysphagia clearly differentiated PD from the APDs, but did not help distinguish different APDs. Survival after onset of dysphagia was similarly poor among all parkinsonian disorders. Evaluation and adequate treatment of patients with PD who complain of dysphagia might prevent or delay complications such as aspiration pneumonia, which in turn may improve quality of life and increase survival time.

What is the accuracy of the clinical diagnosis of multiple system atrophy? A clinicopathologic study.

BACKGROUND: The presentation of symptoms for multiple system atrophy (MSA) varies. Because there are no specific markers for its clinical diagnosis, the diagnosis rests on the results of the neuropathologic examination. Despite several clinicopathologic studies, the diagnostic accuracy for MSA is unknown. OBJECTIVES: To determine the accuracy for the clinical diagnosis of MSA and to identify, as early as possible, those features that would best predict MSA. DESIGN: One hundred five autopsy-confirmed cases of MSA and related disorders (MSA [n=16], non-MSA [n=89]) were presented as clinical vignettes to 6 neurologists (raters) who were unaware of the study design. Raters identified the main clinical features and provided a diagnosis based on descriptions of the patients' first and last clinic visits. METHODS: Interrater reliability was evaluated with the use of kappa statistics. Raters' diagnoses and those of the primary neurologists (who followed up the patients) were compared with the autopsy-confirmed diagnoses to estimate the sensitivity and positive predictive values at the patients' first and last visits. Logistic regression analysis was used to determine the best predictors to diagnose MSA. RESULTS: For the first visit (median, 42 months after the onset of symptoms), the raters' sensitivity (median, 56%; range, 50%-69%) and positive predictive values (median, 76%; range, 61%-91%) for the clinical diagnosis of MSA were not optimal. For the last visit (74 months after the onset of symptoms), the raters' sensitivity (median, 69%; range, 56%-94%) and positive predictive values (median, 80%; range, 77%-92%) improved. Primary neurologists correctly identified 25% and 50% of the patients with MSA at the first and last visits, respectively. False-negative and -positive misdiagnoses frequently occurred in patients with Parkinson disease and progressive supranuclear palsy. Early severe autonomic failure, absence of cognitive impairment, early cerebellar symptoms, and early gait disturbances were identified as the best predictive features to diagnose MSA. CONCLUSIONS: The low sensitivity for the clinical diagnosis of MSA, particularly among neurologists who followed up these patients in the tertiary centers, suggests that this disorder is underdiagnosed. The misdiagnosis of MSA is usually due to its confusion with Parkinson disease or progressive supranuclear palsy, thus compromising the research on all 3 disorders.