Journal of Alzheimer's Disease - Volume 60, issue 4

Authors: Castellani, Rudy J. | Perry, George

Article Type: Review Article

Abstract:  Extensive exposure of boxers to neurotrauma in the early 20th century led to the so-called punch drunk syndrome, which was formally recognized in the medical literature in 1928. “Punch drunk” terminology was replaced by the less derisive ‘dementia pugilistica’ in 1937. In the early case material, the diagnosis of dementia pugilistica required neurological deficits, including slurring dysarthria, ataxia, pyramidal signs, extrapyramidal signs, memory impairment, and personality changes, although the specific clinical substrate has assumed lesser importance in recent years with a shift in focus on molecular pathogenesis. The postmortem neuropathology of dementia pugilistica has also evolved substantially over the past …90 years, from suspected concussion-related hemorrhages to diverse structural and neurofibrillary changes to geographic tauopathy. Progressive neurodegenerative tauopathy is among the prevailing theories for disease pathogenesis currently, although this may be overly simplistic. Careful examination of historical cases reveals both misdiagnoses and a likelihood that dementia pugilistica at that time was caused by cumulative structural brain injury. More recent neuropathological studies indicate subclinical and possibly static tauopathy in some athletes and non-athletes. Indeed, it is unclear from the literature whether retired boxers reach the inflection point that tends toward progressive neurodegeneration in the manner of Alzheimer’s disease due to boxing. Even among historical cases with extreme levels of exposure, progressive disease was exceptional. Show more

Keywords: Boxing, dementia pugilistica, neurofibrillary degeneration, tauopathy

DOI: 10.3233/JAD-170669

Citation: Journal of Alzheimer's Disease, vol. 60, no. 4, pp. 1209-1221, 2017

Authors: Blonz, Edward R.

Article Type: Research Article

Abstract: The decreased availability of metabolizable energy resources in the central nervous system is hypothesized to be a key factor in the pathogenesis of Alzheimer’s disease. More specifically, the age-related decline in the ability of glucose to cross the blood-brain barrier creates a metabolic stress that shifts the normal, benign processing of amyloid-β protein precursor toward pathways associated with the production of amyloid-β plaques and tau-containing neurofibrillary tangles that are characteristic of the disease. The neuroenergetic hypothesis provides insight into the etiology of Alzheimer’s disease and illuminates new approaches for diagnosis, monitoring, and treatment.

Keywords: Alzheimer’s disease, alpha-secretase, amyloid-β, amyloid-β protein precursor, beta-hydroxy butyrate, beta-secretase, blood-brain barrier, glucose, gamma-secretase, GLUT1, neuroenergetic hypothesis, tau, type-3 diabetes

DOI: 10.3233/JAD-170549

Citation: Journal of Alzheimer's Disease, vol. 60, no. 4, pp. 1223-1229, 2017

Authors: Sakata, Nobuo | Okumura, Yasuyuki

Article Type: Short Communication

Abstract: Early-onset dementia (EOD) affects the employment of patients and family members. To demonstrate how likely employees are to leave their jobs after an EOD diagnosis for themselves or a family member, we conducted a matched cohort study of 143 employees and 77 family members diagnosed with EOD using a claims database. We matched these participants to 5 controls each, and followed them for approximately 600 days. In the employee cohort, patients with EOD were more likely to leave their jobs than were controls (hazard ratio: 2.26). This suggests that healthcare providers should offer employment support to patients just after diagnosis.

Keywords: Claims database, early onset dementia, employment, job loss

DOI: 10.3233/JAD-170478

Citation: Journal of Alzheimer's Disease, vol. 60, no. 4, pp. 1231-1235, 2017

Authors: Woumans, Evy | Versijpt, Jan | Sieben, Anne | Santens, Patrick | Duyck, Wouter

Article Type: Article Commentary

Abstract: In a recent review, Mukadam, Sommerlad, and Livingston (2017) argue that bilingualism offers no protection against cognitive decline. The authors examined the results of 13 studies (five prospective, eight retrospective) in which monolinguals and bilinguals were compared for cognitive decline and onset of dementia symptoms. Analysis of four of the five prospective studies resulted in the conclusion that there was no difference between monolinguals and bilinguals, whereas seven of the eight retrospective studies actually showed bilingualism to result in a four-to-five year delay of symptom onset. The authors decided to ignore the results from the retrospective studies in favor of …those from the prospective studies, reasoning that the former may be confounded by participants’ cultural background and education levels. In this commentary, we argue that most of these studies actually controlled for these two variables and still found a positive effect of bilingualism. Furthermore, we argue that the meta-analysis of the prospective studies is not complete, lacking the results of two crucial reports. We conclude that the literature offers substantial evidence for a bilingual effect on the development of cognitive decline and dementia. Show more

Keywords: Cognitive decline, dementia, multilingualism, prospective cohort studies, retrospective studies

DOI: 10.3233/JAD-170759

Citation: Journal of Alzheimer's Disease, vol. 60, no. 4, pp. 1237-1239, 2017

Authors: Zhang, Ling | Wang, Ying | Xiayu, Xia | Shi, Changhua | Chen, Wei | Song, Nan | Fu, Xinjing | Zhou, Rui | Xu, Yan-Feng | Huang, Lan | Zhu, Hua | Han, Yunlin | Qin, Chuan

Article Type: Research Article

Abstract: The topic of gut microbiota is currently attracting considerable interest as a potential factor in Alzheimer’s disease (AD). However, the extent and time course of alterations in the gut microbiota, and their effects on AD pathology remain uncertain. Herein, we compared the fecal microbiomes and fecal short chain fatty acid composition (SCFAs) between wild-type and AD model mice at different ages under strictly controlled specific pathogen free conditions, and also conducted microscopic investigations of intestinal structures. Our results showed that the microbiota composition and diversity were perturbed and the level of SCFAs was reduced in AD mice, predicting alterations in …more than 30 metabolic pathways, which may be associated with amyloid deposition and ultrastructural abnormalities in AD mouse intestine. These findings indicate that AD pathology might not only affect brain function directly, but also exacerbate cognitive deficits through reducing the level of SCFAs via alterations of gut microbiota induced by intestinal amyloid deposition. Our data may support a role of gut microbiota, and suggest a novel route for therapeutic intervention in AD. Show more

Keywords: aging, Alzheimer’s disease, gut microbiota, mouse model, short chain fatty acids

DOI: 10.3233/JAD-170020

Citation: Journal of Alzheimer's Disease, vol. 60, no. 4, pp. 1241-1257, 2017

Authors: Pongan, Elodie | Dorey, Jean-Michel | Krolak-Salmon, Pierre | Federico, Denis | Sellier, Claire | Auguste, Nicolas | Fabre, Florence | Laurent, Bernard | Trombert-Paviot, Béatrice | Rouch, Isabelle

Article Type: Research Article

Abstract: Background: Previous studies showed that a third of patients living at home entered an institution after hospitalization in Cognitive and Behavioral Units (CBUs). Objective: The main objective of this study was to identify predictors of discharge destination for these patients. The secondary objective was to estimate whether institutionalization can have an impact on a patient’s long-term prognosis. Methods: The study population was selected from the EVITAL study and included 140 participants living at home before hospitalization in CBUs. Factors favoring nursing-home admission were investigated and the impact of discharge destinations (i.e., home or nursing home) on …patients’ prognosis was examined. Results: Institutionalized patients were more likely to be women (F = 4.7; p  = 0.03), with a higher dementia severity (F = 9.82; p  = 0.007), often living alone (F = 19.69; p  = 0.001), with a caregiver other than spouse (F = 8.93; p  = 0.003), and with a higher patient quality of life (QoL) according to the caregiver (F = 11.73; p  = 0.001). When using multivariate logistic linear regressions, we showed a relationship between marital status (OR = 0.19, 95% CI: 0.08–0.43, p  < 0.001), dementia severity (OR = 0.15, 95% CI: 0.03–0.79, p  = 0.03), QoL (OR = 0.88, 95% CI: 0.79–0.98, p  = 0.017), and institutionalization. At three months, a higher overall rate of rehospitalization (F = 12.21; p  < 0.001) and rehospitalization for behavioral and psychological symptoms of dementia (F = 6.76; p  = 0.006) were observed for patients staying at home after CBU discharge. Conclusion: Our study allows for a better understanding of the institutionalization risk factors of the patients hospitalized in CBUs. Identification of these factors could help clinicians to better support patients and to help the transition to be smoother. Moreover, our results suggest that prognosis of institutionalized patients is not unfavorable when compared with patients staying at home. Show more

Keywords: Alzheimer’s disease and related disorders, behavioral and psychological symptoms of dementia, caregivers, institutionalized patients, nursing home placement, predictors

DOI: 10.3233/JAD-170419

Citation: Journal of Alzheimer's Disease, vol. 60, no. 4, pp. 1259-1266, 2017

Authors: DiFrancesco, Jacopo C. | Tremolizzo, Lucio | Polonia, Valeria | Giussani, Giorgia | Bianchi, Elisa | Franchi, Carlotta | Nobili, Alessandro | Appollonio, Ildebrando | Beghi, Ettore | Ferrarese, Carlo

Article Type: Research Article

Abstract: Background: The prevalence of epilepsy with onset in adulthood increases with age, mainly due to the accumulation of brain damage. However, a significant proportion of patients experience seizures of unknown cause. Alzheimer’s disease (AD) is associated with an increased risk of seizures. Seizure activity is interpreted as a secondary event related to hyperexcitability caused by amyloid-β aggregation. Objective: Since neurodegenerative processes begin several years before clinical symptoms, epilepsy could be more frequent in the presymptomatic stages of dementia. Methods: We retrospectively reviewed the prevalence of epilepsy of unknown origin with adult onset before cognitive decline in …a large cohort of AD patients (EPS-AD) recruited based on clinical and neuropsychological data. Data of patients with epilepsy followed by AD were compared with two control groups: patients with AD without seizures (no EPS-AD) and a large reference population (RP). Results: In AD patients, the prevalence of epilepsy of unknown origin, with onset in the adulthood before cognitive decline is 17.1 times higher compared with the RP (95% CI: 10.3–28.3). In EPS-AD, seizures begin on average 4.6 years (median 2.0) before the onset of cognitive symptoms and cognitive decline starts 3.6 years earlier compared with noEPS-AD. Conclusions: Neurodegenerative processes of dementia could play a key role in the pathogenesis of epilepsy in a subgroup of individuals intended to develop cognitive decline. Adult-onset epilepsy of undefined cause could thus represent a risk factor for the ongoing neurodegenerative damage, even preceding by years the onset of clinical symptoms of dementia. Show more

Keywords: Alzheimer’s disease, disease modifying therapies, epilepsy, neurodegeneration, prevalence, seizure

DOI: 10.3233/JAD-170392

Citation: Journal of Alzheimer's Disease, vol. 60, no. 4, pp. 1267-1274, 2017

Authors: Boccardi, Virginia | Conestabile della Staffa, Manuela | Baroni, Marta | Ercolani, Sara | Croce, Michele Francesco | Ruggiero, Carmelinda | Mecocci, Patrizia | The ReGAL study group

Collaborators: Gabelli, C | Codemo, A | Marinelli, K | Capurso, A | Cucinotta, D | Reggiani, A | Ellena, L | Zanetti, O | Putzu, P | Del Prete, M | Spaccamento, S | Abate, G | Di Iorio, A | Cester, A | Formilan, M | Busonera, F | Anzivino, F | Masotti, G | Cavallini, C | Mossello, E | Odetti, P | Cataldi, AG | Estraneo, A | Sica, G | Renna, S | Nicita-Mauro, V | Basile, G | Salvioli, G | Mussi, C | Ascari, S | Casale, R | Frazzitta, G | Scognamiglio, M | Di Palma, A | Rengo, F | Canonico, V | Fortunato, F | Enzi, G | Giordano, M | Vitrano Catania, T | Ferrari, E | Cuzzoni, G | Del Re, ML | Guizzardi, G | Biagini, C | Bavazzano, A | Ferrari, A | Dallari, A | Carbonin, P | Bernabei, R | Silveri, MC | Bartorelli, L | Gandolfi, B | Cerqua, R | Pilotto, A | Cascavilla, L | Chiaranti, A | Marinelli, M | Tripi, G | Gallucci, M | Marchetti, C | Masiello, V | Sacco, D | Ricci, G

Article Type: Research Article

Abstract: Background: Presence of behavioral and psychological symptoms of dementia (BPSD) is very common in subjects with cognitive impairment, representing an important determinant of disease progression, institutionalization, and worse prognosis. Knowledge of the prevalence and correlates of BPSD in community-living old subjects with cognitive impairment is limited so far, but it is essential for establishing specifically tailored care and cure in such a vulnerable population. Objective: With this study, we aimed at investigating, in a large sample of old age subjects with cognitive impairment, BPSD prevalence and correlates including the main demographic, clinical, and socio-environmental characteristics. Methods: …Data were gathered from the ReGAl project (Rete Geriatrica Alzheimer; Geriatric Network on Alzheimer’s disease), a large longitudinal Italian multicentric clinical-based study, promoted by the Italian Society of Gerontology and Geriatrics (SIGG). Results: We evaluated data from 4,157 old-age subjects affected by mild cognitive impairment (MCI) (541; 13%) or dementia (3616; 87%). 85.2% of all the population presented with at least one BPSD. Using a factor analysis, we identified four factors of BPSD: psychotic, affective, maniac, and impulse control behaviors. Logistic regression analyses revealed that among the main demographic, clinical, and socio-environmental aspects considered, only comorbidity was associated with all factors, independently of multiple covariates. Conclusion: Identification of BPSD is crucial in everyday clinical practice and necessary to develop specific interventions and to define appropriate outcomes in their management. BPSD occur in a complex psychopathological context, influenced by several demographic and environmental factors that must be taken into account for a correct diagnosis and treatment. Show more

Keywords: Behavioral disturbances, cognitive impairment, dementia, old age

DOI: 10.3233/JAD-170494

Citation: Journal of Alzheimer's Disease, vol. 60, no. 4, pp. 1275-1283, 2017

Authors: Fischer, Florian U. | Wolf, Dominik | Fellgiebel, Andreas | for the Alzheimer’s Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: Hippocampal atrophy and hypometabolism of the posterior cingulate cortex (PCC), early markers of Alzheimer’s disease (AD), have been shown to be associated in late mild cognitive impairment and early AD via atrophy of connecting cingulum fibers. Recently, a direct association of hippocampal atrophy and PCC hypometabolism has been shown in cognitively normal elderly. We aimed to investigate if this association might be modulated by partly non-hippocampogenic alterations of parahippocampal cingulum (PHC) integrity. 45 cognitively healthy elderly aged 59 to 89 years were included from the Alzheimer’s Disease Neuroimaging Initiative. Hippocampal volumes and PCC glucose metabolism were measured using MRI and …FDG-PET. PHC fibers connecting the hippocampus and the PCC were reconstructed using diffusion weighted MRI and measures of diffusivity were calculated. Using robust linear regression, interaction effects of PHC diffusivity and hippocampal volume on PCC metabolism were calculated. For both hemispheres, significant interaction effects were found for PHC mean diffusivity. Interaction effects were such that the association of hippocampal volume and PCC metabolism was higher in subjects with increased mean diffusivity in PHC fibers. In cognitively normal elderly, compromised integrity of the PHC may increase the risk of PCC hypometabolism due to hippocampal atrophy. Spared PHC fiber integrity may protect against PCC hypometabolism due to hippocampal atrophy. Show more

Keywords: Cingulum, diffusion weighted MRI, fiber tractography, hippocampus, interaction, normal aging, position emission tomography, posterior cingulate cortex

DOI: 10.3233/JAD-170147

Citation: Journal of Alzheimer's Disease, vol. 60, no. 4, pp. 1285-1294, 2017

Authors: Mc Ardle, Ríona | Morris, Rosie | Wilson, Joanna | Galna, Brook | Thomas, Alan J. | Rochester, Lynn

Article Type: Research Article

Abstract: Distinguishing dementia subtypes can be difficult due to similarities in clinical presentation. There is increasing interest in discrete gait characteristics as markers to aid diagnostic algorithms in dementia. This structured review explores the differences in quantitative gait characteristics between dementia and healthy controls, and between four dementia subtypes under single-task conditions: Alzheimer’s disease (AD), dementia with Lewy bodies and Parkinson’s disease dementia, and vascular dementia. Twenty-six papers out of an initial 5,211 were reviewed and interpreted using a validated model of gait. Dementia was associated with gait characteristics grouped by slower pace, impaired rhythm, and increased variability compared to normal …aging. Only four studies compared two or more dementia subtypes. People with AD are less impaired in pace, rhythm, and variability domains of gait compared to non-AD dementias. Results demonstrate the potential of gait as a clinical marker to discriminate between dementia subtypes. Larger studies using a more comprehensive battery of gait characteristics and better characterized dementia sub-types are required. Show more

Keywords: Alzheimer’s disease, biomarker, cognition, cognitive impairment, diagnosis, Lewy body dementia

DOI: 10.3233/JAD-170541

Citation: Journal of Alzheimer's Disease, vol. 60, no. 4, pp. 1295-1312, 2017